Brain, Behavior, and Immunity xxx (2015) xxx–xxx

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Brain, Behavior, and Immunity

journal homepage: www.elsevier.com/locate/ybrbi

Microglial dysfunction connects depression and Alzheimer’s disease

Luís Eduardo Santos a, Danielle Beckman b, Sergio T. Ferreira a,b,⇑
a
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
b
Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: Alzheimer’s disease (AD) and major depressive disorder (MDD) are highly prevalent neuropsychiatric
Received 5 July 2015 conditions with intriguing epidemiological overlaps. Depressed patients are at increased risk of develop-
Received in revised form 19 November 2015 ing late-onset AD, and around one in four AD patients are co-diagnosed with MDD. Microglia are the main
Accepted 19 November 2015
cellular effectors of innate immunity in the brain, and their activation is central to neuroinflammation – a
Available online xxxx
ubiquitous process in brain pathology, thought to be a causal factor of both AD and MDD. Microglia serve
several physiological functions, including roles in synaptic plasticity and neurogenesis, which may be dis-
Keywords:
rupted in neuroinflammation. Following early work on the ‘sickness behavior’ of humans and other ani-
Alzheimer’s disease
Microglia
mals, microglia-derived inflammatory cytokines have been shown to produce depressive-like symptoms
Major depressive disorder when administered exogenously or released in response to infection. MDD patients consistently show
Neuroinflammation increased circulating levels of pro-inflammatory cytokines, and anti-inflammatory drugs show promise
for treating depression. Activated microglia are abundant in the AD brain, and concentrate around senile
plaques, hallmark lesions composed of aggregated amyloid-b peptide (Ab). The Ab burden in affected
brains is regulated largely by microglial clearance, and the complex activation state of microglia may
be crucial for AD progression. Intriguingly, recent reports have linked soluble Ab oligomers, toxins that
accumulate in AD brains and are thought to cause memory impairment, to increased brain cytokine pro-
duction and depressive-like behavior in mice. Here, we review recent findings supporting the inflamma-
tory hypotheses of AD and MDD, focusing on microglia as a common player and therapeutic target linking
these devastating disorders.
Ó 2015 Published by Elsevier Inc.

1. Introduction In the following sections, we examine epidemiological data

Although Alzheimer’s disease (AD) is often regarded solely as a
disease of memory, nearly all patients display behavioral and psy-
chological symptoms that accompany the characteristic memory/
cognitive impairment (Lyketsos et al., 2011, 2002). Those symp-
toms have significant clinical and societal relevance – they increase
the burden on patients and caregivers, precipitate institutionaliza-
tion, and ramp up the costs of managing AD (Allegri et al., 2006;
Hurt et al., 2008; Kales et al., 2015).
Depression is consistently reported as one of the most prevalent
co-morbidities in AD (Lyketsos and Olin, 2002; Steinberg et al.,
2008). Its incidence scales with AD progression (Steinberg et al.,
2008), and a diagnosis of major depressive disorder (MDD) predicts
a poorer cognitive outcome in later life, with increased risk of
developing AD (Ownby et al., 2006).
⇑ Corresponding author at: Institute of Biophysics Carlos Chagas Filho, Federal
University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil.
E-mail address: ferreira@bioqmed.ufrj.br (S.T. Ferreira).
linking depression and AD, and review mechanistic hypotheses
that may explain this connection. We focus on neuroinflammation
and microglial activation, common denominators to a number of
brain-related pathologies thought to be causal factors in both AD
and MDD.
1.1. Epidemiological link between AD and depression
Early assessments of the prevalence of depression in AD
patients date from the 1980s, and showed widely variable results,
ranging from zero to 86% (Knesevich et al., 1983; Merriam et al.,
1988). But after 1990, more consistent epidemiological data began
to emerge. Burns and colleagues published a notable case-register
study of AD patients in the UK, finding that 20% of them were
aggressive, 41% apathetic and 24% depressed (Burns et al., 1990a,
b).
A decade later, cross-sectional analysis of data from the much
larger, US-based ‘Cache County Study on Memory, Health and
Aging’ found similar results. This longitudinal study enrolled
5092 community-dwellers 65 and older, and found that 20% of

http://dx.doi.org/10.1016/j.bbi.2015.11.011
0889-1591/Ó 2015 Published by Elsevier Inc.

Please cite this article in press as: Santos, L.E., et al. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav. Immun. (2015),
http://dx.doi.org/10.1016/j.bbi.2015.11.011
2 L.E. Santos et al. / Brain, Behavior, and Immunity xxx (2015) xxx–xxx

those diagnosed with AD also had depressive symptoms. Non- sample was limited, they further noted that all MCI patients meet-
demented elderly in the same cohort showed a third of this preva- ing DSM-IV criteria for MDD converted to AD within the 3-year
lence (Lyketsos et al., 2000). Working on a subset of data from the follow-up period (Modrego and Ferrández, 2004).
same study (408 dementia cases, 63% AD) Steinberg and colleagues
later concluded that the cumulative prevalence of depression in
1.3. Depression: Risk factor or prodromal symptom of AD?
dementia, over a 5-year period, is 77% (Steinberg et al., 2008). Sev-
eral different cohort studies have since helped establish depression
Even when it manifests before MCI or other cognitive symp-
as one the most frequent behavioral symptoms in AD (Benoit et al.,
toms, depression appears to predict the development of AD. In
2012; Porta-Etessam et al., 2011).
2003, Green and colleagues reported an analysis of data from the
Despite general consensus on the positive correlation between
Multi-institutional Research in Alzheimer’s Genetic Epidemiology
dementia and depression, it should be noted that results from dif-
(MIRAGE) study, a cross-sectional case-control study of 4046 sub-
ferent studies have varied considerably, and higher point preva-
jects—about half probable AD cases, half non-affected family mem-
lence values, of up to 50%, were recently reported (Chi et al.,
bers. That study showed a significant association between
2014; Lee and Lyketsos, 2003; Starkstein et al., 2005; Zubenko
depressive symptoms and the risk for development of AD later in
et al., 2003). Although differences among sampled populations
life. The association was stronger when symptoms appeared up
likely account for a significant part of this variability (Lee and
to 1 year before the onset of AD, but was significant even when
Lyketsos, 2003), the intrinsic difficulty of diagnosing depression
they first occurred more than 25 years before cognitive deficits
in old age may also be an important contributing factor, especially
(Green et al., 2003). These results were later included in a large
when dementia is comorbid (Nelson, 2001). Confounding cognitive
meta-analysis by Ownby and colleagues, which corroborated the
deficits, reduced perception of symptoms and impaired verbal
notion that a history of depression increases the risk of developing
communication complicate diagnosis in older patients (Fiske
AD (Ownby et al., 2006).
et al., 2009). Depression in AD tends to present differently from
Other studies, however, point to depression not as a risk factor,
depression in non-demented elderly, which in turn differs from
but as an early symptom of the neurodegenerative process of AD,
that of younger patients (Chemerinski et al., 2001; Fiske et al.,
advocating an overlap between the neuropathological events caus-
2009; Janzing et al., 2002). To address such differences, authors
ing cognitive deficits and those causing depressive symptoms in
must rely on one of numerous published diagnostic criteria, and
dementia (Kales et al., 2015; Panza et al., 2010; Richard et al.,
their choice of threshold largely defines reported results (Teng
2013). Considerable structural and functional imaging data sup-
et al., 2008).
port this hypothesis, showing that neuropathological lesions in
The 1982 Geriatric Depression Scale (GDS; Yesavage et al.,
AD brains correlate with the development of depressive behavior,
1982) was the first criterion to account for the particularities of
and may underlie them. These pathologies include reduced gray-
late-life depression. The widely used Neuropsychiatric Inventory
matter volume in frontal and temporal lobes (Son et al., 2013),
(NPI; Cummings et al., 1994) was not available until 1994, and only
lesioned subcortical regions (Palmqvist et al., 2011), and reduced
much later, in 2001, the National Institute of Mental Health devel-
glucose metabolism/brain perfusion in the prefrontal cortex
oped its specific diagnostic criteria for depression in AD (PDC-dAD;
(Holthoff et al., 2005; Kang et al., 2012; Kataoka et al., 2010;
Olin et al., 2002). Notably, implementation of PDC-dAD criteria to
Levy-Cooperman et al., 2008; Oshima et al., 2014; Terada et al.,
cohort studies revealed a larger prevalence of comorbid depression
2014).
in AD patients than could be estimated with more generic criteria
Despite the use of distinct diagnostic criteria, follow-up inter-
(Teng et al., 2008; Vilalta-Franch et al., 2006). A shift towards
vals, and sample characteristics, the general consensus emerging
specific, more sensitive diagnostic criteria could thus be related
from epidemiological studies leaves little doubt that depression
to the increasing reported prevalence of depression in AD, as illus-
and AD are tightly related. However, whether depression is a pro-
trated in a recent meta-analysis by Chi and colleagues (Chi et al.,
dromal symptom or a risk factor for AD remains to be determined.
2015).
Interestingly, some have argued that these hypotheses may be
simultaneously true, and that multiple pathways connect depres-
1.2. Depression in mild cognitive impairment
sion and AD (Butters et al., 2008; Green et al., 2003).
Given the long time scale of the association between depression
The prevalence of depression is also disproportionally high
and dementia (e.g. Green et al., 2003), neuroinflammation and
among patients diagnosed with mild cognitive impairment (MCI),
microglial activation appear as potential causal factors to explain
which presents as a relatively mild form of cognitive deficit
the AD-depression link.
between normal aging and dementia. In a systematic review of lit-
erature published before 2007, Apostolova and Cummings found
the prevalence of neuropsychiatric symptoms among MCI patients 2. Microglia function in the normal and diseased brain
to be 35–75%. Depression was listed as one of the most frequent,
with a majority of authors reporting prevalences of 20–50%, Microglia are resident immune cells of the central nervous sys-
depending on sampling and diagnostic criteria (Apostolova and tem (CNS), and account for approximately 10% of the total number
Cummings, 2008). of cells in a healthy mammalian brain (Prinz and Priller, 2014).
Although MCI affects memory to a certain extent, it does not While other major cell populations in the CNS share a neuroepithe-
represent a major impact on daily life activities (Gauthier et al., lial origin, microglia derive from myeloid progenitors, being more
2006). However, while some patients remain stable or even closely related to peripheral macrophages than to neighboring
recover normal cognition, 20–40% of MCI patients progress to AD astrocytes, oligodendrocytes or neurons (Ginhoux et al., 2010).
or other dementias within a few years, a much higher proportion It is now established that microglial progenitors originating in
than in cognitively normal elderly individuals (Roberts and the yolk sac migrate and colonize the CNS during embryonic devel-
Knopman, 2013). Notably, coexistence of depression and MCI opment, before the blood–brain barrier is formed. These progeni-
accelerates cognitive decline, and the risk of developing AD is tors subsequently differentiate and become confined to the CNS,
increased. In a prospective cohort study, Modrego and Ferrández where they function as mononuclear phagocytes, recognizing and
reported that depressed MCI patients had a twofold higher risk scavenging dead cells, pathogens and other targets. Microglia
of developing AD than non-depressed MCI subjects. Although their appear capable of local self-renewal, not depending on recruitment

Please cite this article in press as: Santos, L.E., et al. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav. Immun. (2015),
http://dx.doi.org/10.1016/j.bbi.2015.11.011
 L.E. Santos et al. / Brain, Behavior, and Immunity xxx (2015) xxx–xxx
of circulating progenitors to maintain its population (Ajami et al.,
2007; Casano and Peri, 2015; Kierdorf et al., 2013).
Microglia are well known for their role as cellular effectors of
innate immunity; together with astrocytes, they drive the neuroin-
flammatory process, through phagocytosis and cytokine release.
However, this comprises only part of their function in the CNS.
Under physiological conditions and in the absence of inflammatory
stimuli, microglia are found in what is often called a ‘resting state’,
morphologically defined by extended and ramified processes. Far
from being dormant or inactive, however, these so-called resting
microglia are highly dynamic. Retracting and expanding their
processes in response to environmental cues, they interact with
blood vessels, neurons and astroglia, in constant surveillance of
the environment (Nimmerjahn et al., 2005). In fact, many authors
have become critical of the word ‘resting’, preferring instead to
use an alternative term, ‘surveillant microglia’ (Chen and Trapp,
2015).
Recent work has highlighted the importance of microglial
surveillance to CNS function. In early postnatal development, the
elimination of excess synapses – a process known as synaptic prun-
ing – was shown to be dependent on microglia. Paolicelli et al.
(2011) reported that mice lacking the fractalkine receptor (CX3CR1
KO), which suffer a transient reduction in brain microglia, had con-
current synaptic pruning deficits, resulting in an abnormally high
number of dendritic spines. Work on CX3CR1 KO mice also helped
establish a role of microglia in functional maturation of synapses
(Paolicelli et al., 2011; Paolicelli and Gross, 2011). Most notably,
pruning deficits found in this model of microglial dysfunction were
implicated in behavioral abnormalities, including impaired social
interaction and autistic-like behavior (Zhan et al., 2014).
In addition to its role in circuit refinement, physiologically
active microglia modulate neuronal activity in the adult brain
through direct contact with neurons (Li et al., 2012). Interestingly,
a novel type of microglia–neuron interaction was recently
described in the adult mouse brain, with a subpopulation of micro-
glia shown to specifically bind to the axon initial segment of corti-
cal neurons. While the importance of this particular interaction to
neuronal function is not yet clear, it is of note that it is lost after
brain injury (Baalman et al., 2015). This observation reinforces
the role of surveillance microglia in brain physiology, and the
notion that a ‘loss-of-function’ effect takes place in pathology.
Indeed, physiological functions depending on microglial shape,
local interactions or secretory profile may become impaired as
microglia undergo changes associated with inflammation and
pathology, briefly described below.
2.1. The M1–M2 dichotomy
In both acute CNS lesions and chronic neurological diseases,
microglia become activated, gradually changing morphology and
function. The relevance of microglial activation and subsequent
proliferation in many pathological contexts has been studied
extensively in the past decades, and is discussed in a number of
excellent recent reviews (e.g.: Heneka et al., 2014; Hu et al.,
2014; Lynch, 2014; Perry and Holmes, 2014; Von Bernhardi
et al., 2010; Yirmiya et al., 2015).
Activated microglia acquire an amoeboid shape, with a larger
cell body and retracted processes. Functionally, this phenotypic
change was initially classified according to the same paradigm
used for peripheral macrophages. According to this view, an initial
stimulus elicits an ‘M1’ response, centered around the production
and release of mostly pro-inflammatory cytokines, such as TNF-a
and IL-6. With persisting stimulation, microglia may move towards
an alternative activation pattern, the so-called ‘M2’ state, which
involves active phagocytosis and release of factors regarded as
Please cite this article in press as: Santos, L.E., et al. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav. Immun. (2015),
http://dx.doi.org/10.1016/j.bbi.2015.11.011
3
anti-inflammatory (reviewed in Casano and Peri, 2015; Hu et al.,
2014).
Historically, reports have focused on the detrimental conse-
quences of microglia-mediated neuroinflammation, often shown
to exacerbate neuronal damage and hinder functional recovery
after injury. However, it is now clear that a more complex scenario
exists, in which microglial activation may also protect the lesioned
brain, depending on context and timeframe (Hellwig et al., 2013).
This matter has been surrounded by controversy in the literature,
largely due to the M1–M2 dichotomy; a persisting notion now
increasingly regarded as overly simplistic, and not necessarily fit
to encompass all microglial phenotypes (Chen and Trapp, 2015;
Mittelbronn, 2014). Although some authors may be inclined to
describe all M2-like microglia as neuroprotective (and, conversely,
M1-like microglia as potentially detrimental), relevant details are
lost under this classification, which must be used with caution
and in context. It may be possible for microglia to display M1
and M2 phenotypic characteristics simultaneously (Fenn et al.,
2014), and an M2-like phenotype does not always result in neuro-
protection (Cherry et al., 2014).
3. Neuroinflammation and the role of microglia in Alzheimer’s
disease
Alzheimer’s disease (AD), the most common form of dementia
of the elderly, affects more than 35 million people worldwide (Alz-
heimer’s Association, 2015) and is clinically characterized by cog-
nitive deficits and memory loss. Although recent advances
towards diagnostic procedures have been made (Clark et al.,
2011; Curtis et al., 2015; Doecke et al., 2012; Klunk et al., 2004;
Mapstone et al., 2014; Sabri et al., 2015; Viola et al., 2014), defini-
tive diagnosis of AD still relies on histopathology. Plaques largely
composed of fibrillar aggregates of the amyloid-b peptide (Ab)
and neurofibrillary tangles made up from hyperphosphorylated
tau protein are the defining lesions found in AD-affected brains,
and they are always accompanied by diffuse neuroinflammation.
There is now little doubt that this inflammatory component is
an important player in the pathogenesis of AD (reviewed in
Wilcock, 2012). However, it is still not clear whether brain inflam-
mation is a consequence of disease progression, a compensatory or
beneficial response, or a causal factor. Evidence supporting the lat-
ter possibility was recently summarized by Krstic and Knuesel
(2013) in what they called the ‘inflammation hypothesis of AD’.
This hypothesis incorporates correlations between late-onset AD
and polymorphisms in genes of the innate immune system, as well
as animal and human studies linking inflammatory mediators to
cognitive decline.
3.1. Inflammatory links
Traumatic brain injury (TBI) is a common primary cause of neu-
roinflammation (Ziebell and Morganti-Kossmann, 2010), known to
increase the risk of developing AD (Green et al., 2003; Lee et al.,
2013). Nonetheless, the possibility that cognitive deterioration fol-
lowing brain trauma could be caused by direct neuronal loss
(related, for example, to localized ischemia or excitotoxicity)
makes it difficult to determine the specific role of TBI-induced
inflammation in the functional outcomes of patients. Interestingly,
however, clinical and preclinical studies suggest that systemic
inflammation, brought about by conditions not involving the
CNS, can also contribute to neurodegeneration and influence the
incidence and progression of AD (Ferreira et al., 2014; Holmes
et al., 2009; Perry et al., 2007;). For example, using data from over
6000 community-dwelling older adults enrolled in the Rotterdam
Study, Ott and colleagues showed that AD prevalence is signifi-
4 L.E. Santos et al. / Brain, Behavior, and Immunity xxx (2015) xxx–xxx
cantly higher among subjects with type 2 diabetes (T2D), a condi-
tion characterized by long-lasting, low grade peripheral inflamma-
tion, and that incidence of AD is almost doubled when T2D is
pre-existing (Ott et al., 1999, 1996).
In chronically inflamed patients, such as those suffering from
obesity and T2D, mechanisms triggered by inflammation may be
shared by the brain and the periphery, and have been proposed
as likely links between AD and peripheral metabolic deregulation
(reviewed in De Felice and Ferreira, 2014; Ferreira et al., 2014;
Heneka et al., 2015b; Morales et al., 2014).
3.2. Microglial priming
The notion that systemic inflammation influences brain disease
is, to a good extent, based on microglial priming. Chronic low grade
peripheral inflammation results in increased levels of inflamma-
tory mediators, notably TNF-a and IL-1b, sufficient to transiently
activate microglia into a primed state (Cunningham, 2013). As
mentioned above, activated microglia go through morphological
changes and express certain types of cell surface antigens and cyto-
kines. Primed microglia do not actively release cytokines, but
retain several markers of activation (Perry and Holmes, 2014).
When presented with a secondary stimulus, primed microglia are
hypersensitive, producing an amplified – and more often neuro-
toxic – response, compared to naïve microglia (Norden et al.,
2015; Perry and Holmes, 2014). Even in the absence of trauma or
pathology, microglia priming may occur as a consequence of nor-
mal aging (Luo et al., 2010). A modest but persistent increase in
plasma levels of pro-inflammatory cytokines is associated with
aging, and could partially account for the increased susceptibility
to AD and other neurodegenerative disorders in older subjects.
Age is, indeed, the strongest risk factor known for AD (Michaud
et al., 2013; Ye and Johnson, 1999).
3.3. Microglia in Ab clearance
Surface receptors found in activated microglia include many
proteins capable of binding soluble Ab, such as the scavenger
receptor SR-AI, toll-like (TLR2, TLR4, TLR6 and TLR9) and comple-
ment receptors. Binding of Ab appears to be often followed by
phagocytosis, proteolysis and Ab clearance, events considered ben-
eficial in AD (Doens and Fernández, 2014; Heneka et al., 2015a). In
addition, bound microglia may prevent the expansion of amyloid
plaques and protofibrils, by forming a barrier that alters their com-
position and toxicity (Condello et al., 2015). Nonetheless, the
increase in microglia recruitment and proliferation that takes place
in AD seems insufficient to halt brain accumulation of Ab. In fact,
Ab clearance is reduced in late-onset AD patients, when compared
to age-matched controls, while Ab production is similar in both
groups (Mawuenyega et al., 2010). Recent studies further indicate
that direct transport across the blood–brain barrier accounts for

25% of the clearance of Ab from the brain, with an additional
25% resulting from transport into the cerebrospinal fluid and sub-
sequent reabsorption into the venous circulation (Roberts et al.,
2014), implying that 50% of total Ab clearance depends on intrac-
erebral degradation. Studies in transgenic mouse models suggest
that microglia become dysfunctional in late-stage AD, with a pro-
gressive reduction in the expression of Ab-binding receptors and
degrading enzymes, while maintaining production of pro-
inflammatory cytokines. These cytokines may, in turn, downregu-
late microglial enzymes, further impairing Ab clearance
(Hickman et al., 2008; Orre et al., 2014).
The triggering receptor expressed on myeloid cells 2 (TREM2) is
one of the receptors more recently implicated in Ab clearance. It is
a cell-surface protein of the immunoglobulin superfamily, highly
expressed in microglia, and known to be involved in the
Please cite this article in press as: Santos, L.E., et al. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav. Immun. (2015),
http://dx.doi.org/10.1016/j.bbi.2015.11.011
phagocytosis of apoptotic neurons (Colonna, 2003; Hsieh et al.,
2009). Although TREM2 was not shown to bind Ab directly, it inter-
acts with myelin phospholipids (Cannon et al., 2012), which asso-
ciate with Ab (Rivest, 2015). Recently, genome-wide association
studies (GWASs) showed that a polymorphism in TREM2 correlates
with increased risk of developing sporadic AD, to an extent similar
to what is seen with the APOEe4 allele (Guerreiro et al., 2013;
Jonsson et al., 2013; Karch et al., 2014), the most relevant genetic
risk factor known to date for sporadic AD (Hauser and Ryan,
2013; Saunders et al., 1993).
A few years before TREM2 polymorphisms were first described
in AD patients, Frank and co-workers (2008) showed that its
expression is increased in microglia associated with amyloid pla-
ques in a transgenic mouse model of AD. In similar models, others
had shown that one of the consequences of TREM2 upregulation in
microglia is reduced production of pro-inflammatory cytokines
(Takahashi et al., 2005; Turnbull et al., 2006). Notably, experiments
using TREM2 knockout mice also carrying AD-related APP/PS1
mutations showed that deletion of even a single copy of the Trem2
gene is sufficient to reduce plaque-associated microglia (Ulrich
et al., 2014). Similar transgenic mice were used to demonstrate
that expression of TREM2 is required for the survival of Ab-
activated microglia, and that its deficiency impacts microgliosis
and efficient Ab clearance (Wang et al., 2015). Interestingly, how-
ever, in another recent paper, Jay and colleagues (2015) reported
opposite results in TREM2-deficient AD mice, which exhibited
reduced inflammation and milder amyloid and tau pathologies.
Although these two studies used different AD animal models lack-
ing TREM2, such markedly different results appear difficult to rec-
oncile. Experiments involving behavioral and cognitive analyses
may help resolve these discrepancies (Rivest, 2015).
Currently available data thus point to a dual role of microglia
and inflammation in AD. Decreased microglia-mediated Ab clear-
ance was shown to be detrimental in a number of models. It causes
early mortality in a transgenic mouse model of AD (El Khoury et al.,
2007), and is likely linked to disease onset in humans, as suggested
by data on TREM2 polymorphisms (Jonsson et al., 2013). This
notion is further corroborated by recent work showing that IL-10,
the prototypical anti-inflammatory cytokine, may in fact nega-
tively impact AD brains, precisely due to its effects on microglia.
Complementary results from two independent groups showed, in
mouse models of AD, that IL-10 overexpression impairs microglial
clearance of Ab (Chakrabarty et al., 2015), while knocking-out IL-10
has the opposite effect, markedly reducing amyloidosis (Guillot-
Sestier et al., 2015). In both reports, significant behavioral and bio-
chemical consequences were found to accompany IL-10 modula-
tion of microglia. Nonetheless, beneficial functions of microglia in
Ab clearance seem to wane in late AD, and continued production
of TNF-a and other pro-inflammatory cytokines is ultimately neu-
rotoxic. This dual role may be one of the reasons why, to date, clin-
ical trials of several anti-inflammatory therapies have failed to
slow AD progression (Perry and Holmes, 2014).
A successful approach to AD-related inflammation should pro-
mote microglial clearance of Ab, while also mitigating the effects
of pro-inflammatory cytokines such as TNF-a. Pharmacological
strategies targeting TREM2 or its downstream effectors may prove
promising in this regard.
4. Microglia deregulation in depression
Some of the earliest associations between inflammation and
depressive symptoms were described in the late 1980s. In clinical
trials aimed at hepatitis and metastatic cancer, immunomodula-
tion strategies based on administering the cytokines IFN-a
(Renault, 1987) and IL-2 (Denicoff et al., 1987) caused unexpected
 L.E. Santos et al. / Brain, Behavior, and Immunity xxx (2015) xxx–xxx
psychiatric outcomes, including mood alterations and depressive
behavior, in a significant subset of patients. In 1991, Smith was
the first to formally propose that inflammatory cytokines could
be the natural cause of MDD, in what he termed ‘The macrophage
theory of depression’.
Around the same time, the term ‘sickness behavior’ was being
coined, to describe behavioral alterations in animals stricken by
viral or bacterial infections. Hart (1988) aggregated observations
that anorexia, sleepiness, reduced grooming and an overall
depressive-like state were common traits of sick and feverish
mammals. Based on his work and that of others, Hart suggested
such behavior was linked to cytokine release, and that it could be
evolutionarily advantageous, perhaps a deterrent to debilitated
animals against certain dangerous activities. Evidence that sick-
ness behavior was indeed mediated by inflammatory cytokines
came a few years later (Kent et al., 1992).
A clearer association between sickness behavior and MDD was
established in 1996, when Yirmiya used LPS-injected rats to show
both phenomena share a common mechanism, involving the
release of inflammatory cytokines. In 2001, Reichenberg and co-
workers extended those results and conclusions to human sub-
jects. Since then, several lines of evidence have corroborated this
connection (reviewed in Dantzer et al., 2008; Irwin and Miller,
2007; Walker, 2013), leading to the current notion that microglia
are intimately connected to mechanisms implicated in depression
(Yirmiya et al., 2015).
4.1. Inflammatory links
Several central and peripheral conditions are correlated with
increased incidence of MDD, including TBI, stroke, T2D and multi-
ple sclerosis (Anisman and Hayley, 2012; Jorge et al., 2004; Naranjo
et al., 2011; Pascoe et al., 2011; Sadovnick et al., 1997). Inflamma-
tory mediators are common to all these pathologies, and have been
proposed as causal links to MDD (Anisman and Hayley, 2012;
Dowlati et al., 2010; Felger and Lotrich, 2013). In line with this pos-
sibility, depressed patients present significantly increased levels of
pro-inflammatory cytokines, notably IL-6 and TNF-a, in both
plasma and CSF (e.g. Alesci et al., 2005; Grassi-Oliveira et al.,
2009; reviewed in Raison et al., 2006). As suggested by this cyto-
kine profile, microglial activation and neuroinflammation are also
increased in the brains of patients undergoing major depressive
episodes. This was recently confirmed in a neuroimaging study
involving depressed subjects with no concurrent psychiatric condi-
tions, and who had been medication-free for at least 6 weeks
(Setiawan et al., 2015). Such correlative data, however, are still
insufficient to determine whether microglial activation is a con-
tributing cause or a consequence of other aspects of MDD
pathology.
Notably, and unlike what has been found for AD, anti-
inflammatory drugs have shown positive results as adjunct thera-
pies for MDD (Akhondzadeh et al., 2009; Köhler et al., 2014;
Müller, 2010). Further, selective 5-HT reuptake inhibitors (SSRIs),
widely prescribed as antidepressants, were found to have potent
anti-inflammatory effects in pre-clinical and clinical studies
(Powell et al., 2013; Sacre et al., 2010; Taraz et al., 2013). Initially
described in peripheral inflammation (Mårtensson and Nässberger,
1993; Roumestan et al., 2007), the anti-inflammatory actions of
SSRIs are now known to extend to microglial function, inhibiting
TNF-a and nitric oxide production (Su et al., 2015; Tynan et al.,
2012; Zhang et al., 2012). Moreover, Macchi and co-workers
(2013) found that animals with partial deletions in the serotonin
transporter (SERT) gene have increased levels of serum pro-
inflammatory cytokines and increased microglial activation,
whether or not under inflammatory stress. Microglial 5-HT recep-
tors have only recently began to be described, and their functions
Please cite this article in press as: Santos, L.E., et al. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav. Immun. (2015),
http://dx.doi.org/10.1016/j.bbi.2015.11.011
5
are largely unknown (Glebov et al., 2015; Kolodziejczak et al.,
2015; Krabbe et al., 2012). Nevertheless, these observations sug-
gest an interesting connection between the modulation of micro-
glial inflammatory responses by 5-HT and the anti-depressant
effects of SSRIs.
4.2. Microglial regulation of neurogenesis
The presence of neurotransmitter receptors in microglia illus-
trates their functional connection to neurons, which is greater than
initially thought (Pocock and Kettenmann, 2007). Another relevant
aspect of this connection, which could further causally link inflam-
mation to MDD, is neurogenesis. Adult hippocampal neurogenesis
was first reported in the human brain in 1998 (Eriksson et al.,
1998), and its inhibition was soon proposed as a mechanism for
MDD (Jacobs et al., 2000). Findings supporting this notion at the
time included the positive regulation of neurogenesis by 5-HT
and its negative regulation by stressful events, likely due to ele-
vated glucocorticoid levels (Kempermann, 2002; Kempermann
and Kronenberg, 2003). Recent data have confirmed and extended
these observations by showing that MDD patients have smaller
hippocampi, and a reduced number of granule cells in the dentate
gyrus (Bremner et al., 2000; Videbech, 2004). Further, it is increas-
ingly clear that SSRIs promote adult neurogenesis in mice and
humans, and that this has a role in their antidepressant effects
(Boldrini et al., 2012, 2013).
The involvement of microglia in this scenario was assessed
early on (Ekdahl et al., 2003). Experiments were likely motivated
not only by the responsiveness of microglia to 5-HT or cytokine
levels, but also by their influence on neural precursor cells. At
the time, in vitro use of conditioned media had begun to show that
factors secreted by microglia guide the differentiation of adult and
embryonic neural precursors towards a neuronal fate (Aarum et al.,
2003), an observation reproduced and expanded by several others
since then (Morgan et al., 2004; Ribeiro Xavier et al., 2015; Walton
et al., 2006).
In line with these early data, it is now known that, under certain
conditions, microglia may adopt a pro-neurogenic phenotype,
which involves the expression of neurotrophins and anti-
inflammatory cytokines, such as insulin-like growth factor 1
(IGF-1), brain derived neurotrophic factor (BDNF), and IL-4 (Chen
and Trapp, 2015; Parkhurst et al., 2013; Ribeiro Xavier et al.,
2015). However, in pro-inflammatory activation states, microglia
are usually described as inhibitory to neurogenesis (Monje et al.,
2003; Nakanishi et al., 2007: Kreisel et al., 2014). The implications
of this dual role may be interesting. While, in most cases, reduced
neurogenesis offers a link between inflammatory microglia,
peripheral disorders and depressive symptoms, certain microglial
activation states could in fact lead to mood improvement. Favoring
these pro-neurogenic states pharmacologically could thus be a
novel road to MDD therapy (Aarum et al., 2003; Gemma and
Bachstetter, 2013; Morgan et al., 2004; Ziv et al., 2006; Ziv and
Schwartz, 2008).
4.3. The IDO hypothesis
An additional mechanism that may link microglial activation to
MDD has been suggested by several authors (e.g. Myint and Kim,
2003; Wichers and Maes, 2004), and more recently revisited by
Dantzer and co-workers (2008). This hypothesis is based on the
observation that increased levels of pro-inflammatory cytokines
induce microglial expression of indolamine-2,3-dioxygenase
(IDO), the enzyme responsible for converting tryptophan to
kynurenine. Tryptophan is the precursor amino acid for serotonin
(5-HT) biosynthesis, and its reduced availability due to kynurenine
production could impair 5-HT synthesis, leading to depressive
6 L.E. Santos et al. / Brain, Behavior, and Immunity xxx (2015) xxx–xxx

behavior. This is supported by the fact that 5-HT depletion pro-
duces depressive-like symptoms in animal models (O’Connor
et al., 2009) and mood alterations in humans (Ruhé et al., 2007),
at least in subjects with a family history of MDD, or in remission.
Alternatively, MDD could be linked to metabolic products of
excessive kynurenine, which include 3-hydroxykynurenine, a free
radical donor, and quinolinic acid, a specific NMDAR agonist. In line
with this hypothesis, increased levels of microglial quinolinic acid
(Steiner et al., 2011) and oxidative products (Ng et al., 2008) have
been reported in MDD patients. Despite considerable amount of
work in this regard (reviewed in Dantzer and Walker, 2014;
Müller and Schwarz, 2007), the exact involvement of excitotoxicity
and the glutamatergic system in this context is not fully under-
stood, and would be beyond the scope of the current review. How-
ever, these results illustrate that the role of IDO and microglia in
MDD may involve multiple neurotransmitter systems.
5. Connecting neuroinflammation and depression in
Alzheimer’s disease
Microglia are a major source, as well as a target, of inflamma-
tory cytokines in the CNS. These cells play a pivotal role in neuroin-
flammation, and several lines of evidence now implicate them in
the incidence and progression of AD (Lynch, 2014) and MDD
(Yirmiya et al., 2015).
A vast literature encompassing clinical studies and basic
research has established that increased levels of microglia-
derived cytokines correlate with AD and depression. For example,
two recent meta-analyses have highlighted the fact that increased
TNF-a and IL-6 levels in peripheral blood correlate robustly with
MDD (Dowlati et al., 2010), and that increased levels of IL-6,
TNF-a, IL-1b, TGF-b, IL-12 and IL-18 correlate with AD
(Swardfager et al., 2010). Further, polymorphisms in genes coding
IL-1b and TNF-a have been linked to increased susceptibility to
both AD (Laws et al., 2005; Sciacca et al., 2003; Wang, 2015) and
depression (Bufalino et al., 2013). In addition, IL-6 polymorphisms,
also risk factors for AD (Chen et al., 2012; Dai et al., 2012), were
linked to impaired therapeutic response in depressed patients
(Bufalino et al., 2013).
More recently, similar observations were extended to AD
patients with comorbid depression. In a study of 55 AD cases —
31 of whom were depressed — and 37 age-matched controls,
Khemka and co-workers found that depressed AD patients had
the highest levels of circulating IL-6 and TNF-a, followed by non-
depressed AD patients and by non-demented controls. Levels of
IL-1b were significantly increased in all AD patients, regardless of
depression status. Further, AD patients with depression exhibited
a positive correlation between cognitive deficits and cytokine
levels (Khemka et al., 2014).
Likewise, type 2 diabetes (T2D), a disorder known for its ties to
systemic inflammation (De Felice and Ferreira, 2014), significantly
increases the risk of AD in depression. In an epidemiological study
involving data collected from all Danish citizens over 50 years of
age (nearly 14 million person-years), Katon and colleagues recently
showed that the incidence of AD is higher in patients with comor-
bid T2D and depression than in those with either condition alone
(Katon et al., 2015). Nonetheless, T2D, depression and AD are com-
plex disorders, and their connections may also involve other mech-
anisms in addition to inflammation, as outlined below.
5.1. IGF-1
Insulin-like growth factor 1 (IGF-1) is a hormone similar to
insulin in structure and biological actions. In the CNS, proliferative
microglia are an important source of IGF-1, which serves as a
trophic factor for maintaining neuronal survival in the cortex dur-
ing development (Ueno et al., 2013) or near sites of lesions
(Lalancette-Hébert et al., 2007). Microglia-derived IGF-1 has sev-
eral important functions, but chronic neuroinflammation and
pro-inflammatory cytokines are capable of reducing its production,
as well as production of other factors secreted by microglia. Such a
suppression is currently regarded a likely facet of the neurodegen-
erative process of AD (Álvarez et al., 2007).
Obesity and peripheral insulin resistance appear linked to lower
IGF-1 levels (Dunger et al., 2003). Interestingly, brain insulin resis-
tance has emerged as an early finding in AD, which is notably
accompanied by changes in the IGF-1 pathway and increased
expression of IGF-1 receptor (IGF-1R) in areas surrounding amyloid
plaques (Bomfim et al., 2012; De Felice, 2013; De Felice et al., 2014;
Moloney et al., 2010; Talbot et al., 2012). Circulating levels of IGF-1
are reduced in AD patients (Carro and Torres-Aleman, 2004;
Watanabe et al., 2005), and recent epidemiological data suggest
that low IGF-1 levels are associated with increased risk of AD
(Westwood et al., 2014). High IGF-1 levels, on the other hand, pre-
serve cognitive function and total brain volume in elderly subjects
(Okereke et al., 2006; Westwood et al., 2014).
In animal models of AD, increasing circulating levels of IGF-1
accelerates Ab clearance, an effect countered by TNF-a (Carro
et al., 2002). In addition, a recent study, using mice injected into
the lateral ventricle with the Ab peptide, showed that reducing
neuroinflammation by deleting the prostaglandin receptor Ep2
enhances IGF-1R signaling (Johansson et al., 2014). IGF-1R is highly
expressed in the hippocampus and other areas relevant for cogni-
tion and mood, where it regulates neuronal plasticity, neurogene-
sis and oxidative balance (Sonntag et al., 2013; Sun, 2006; Yuan
et al., 2015). Chronic systemic or hippocampal IGF-1 deficiency
produces depressive symptoms in mice (Mitschelen et al., 2011),
while administering IGF-1 exerts antidepressant effects in animal
models of depressive behavior (Malberg et al., 2007; Park et al.,
2011; Paslakis et al., 2012). Further, studies in mice suggest that
treatment with IGF-1 reduces sickness behavior caused by LPS or
TNF-a injections (Bluthé et al., 2006; Dantzer et al., 1999), possibly
through increased serotoninergic transmission and neurogenesis
(Hoshaw et al., 2008; Yuan et al., 2015).
Notably, several authors have recently pointed out that
increased IGF-1 levels may also counter depressive symptoms in
humans (Cassilhas et al., 2010; Kopczak et al., 2015; Szczêsny
et al., 2013). In a recent cross-sectional study, direct association
between depressive symptoms and cognition was related to low
IGF-1 levels, suggesting that IGF-1 could also mediate the connec-
tion between memory deficits and depression (Lin et al., 2014).
5.2. BDNF
Brain-derived neurotrophic factor (BDNF), the most widely dis-
tributed neurotrophin in the CNS, is critically involved with struc-
ture and function of neural circuits throughout life. During
development, it regulates progenitor survival, neurogenesis and
synaptogenesis (Barnabé-Heider and Miller, 2003; Martínez et al.,
1998), and its trophic roles, e.g. in the promotion of growth and
stabilization of dendritic spines, extend into adult life (Choi et al.,
2009; Rauskolb et al., 2010). Although it is mostly released by neu-
rons, BDNF may also be produced by microglia (Dougherty et al.,
2000) and astrocytes (Parpura and Zorec, 2010). A recent study
showed an interesting role of microglial BDNF in microglia–neuron
signaling, involving activation of neuronal tropomyosin receptor
kinase B (TrkB) receptors. This interaction promotes learning-
related synapse formation, suggesting that BDNF secreted by
microglia modulates synapses and their plasticity, particularly dur-
ing learning tasks (Parkhurst et al., 2013).

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 L.E. Santos et al. / Brain, Behavior, and Immunity xxx (2015) xxx–xxx
BDNF has emerged as a central molecule in memory formation,
and a potential therapeutic target for cognitive deficits. Its expres-
sion is reduced in a number of pathological conditions (Lu et al.,
2013). Reduced levels of BDNF, pro-BDNF and their corresponding
mRNAs are well documented in AD, even at early stages, in brain
regions such as the hippocampus and cerebral cortex (Holsinger
et al., 2000; Peng et al., 2005). In peripheral blood, BDNF concentra-
tion is lowered in AD and other neurological disorders (Laske et al.,
2007; Ventriglia et al., 2013; Yasutake et al., 2006).
Reduced levels of serum BDNF have been reported consistently
in MDD patients (Bocchio-Chiavetto et al., 2010; Karege et al.,
2002; Molendijk et al., 2014), and the role of BDNF in MDD is well
established (Yu and Chen, 2011), particularly in aging (Dwivedi,
2013). Notably, successful treatment with antidepressants restores
BDNF levels in MDD patients (Wolkowitz et al., 2011).
Neuroinflammation has a known impact on BDNF expression,
first reported in animal experiments utilizing administration of
exogenous cytokines (Lapchak et al., 1993), and now regarded as
a potential factor in the pathophysiology of BDNF-related disorders
(Mondelli et al., 2011). The exact role of microglia-derived BDNF is
not yet established in the context of inflammation. However,
down-regulation of BDNF levels in the brain may be a downstream
event to inflammatory processes mediated by microglia, and a
common underlying contributor to AD and MDD.
5.3. Serotonin and neurogenesis
Involvement of the monoaminergic system in MDD was initially
proposed by Schildkraut, in 1965 (Schildkraut, 1965), who at the
time focused entirely on catecholamines. Shortly after, Coppen
highlighted the role of the serotonergic system (Coppen, 1967),
suggesting that 5-HT deficit is the major cause of depression, and
that effective pharmacological treatment for depression could be
attributed to increased 5-HT at the synaptic cleft. Since then, sero-
tonergic deficits have been associated with various aspects of MDD
pathophysiology. However, this simplistic hypothesis has been
challenged by a number of conflicting results, paving the way for
criticism (Holtzheimer and Mayberg, 2011; Lacasse and Leo,
2005). As a consequence, the 5-HT hypothesis of depression has
been refined in an attempt to account for its inconsistencies, which
include the fact that two thirds of patients remain symptomatic
after treatment with 5-HT-related drugs (Rush et al., 2006;
Trivedi et al., 2006).
Current evidence links depressive episodes to several other
alterations, including hyper-activation of the HPA axis, increased
glucocorticoid release (Pariante and Lightman, 2008), and systemic
inflammation, with increased pro-inflammatory cytokine produc-
tion. These and other findings support what has been called the
‘new 5-HT hypothesis of depression’ (Maes et al., 2011), which sug-
gests new pathways in the search for antidepressants (Berton and
Nestler, 2006). Given its involvement in MDD and its links to mem-
ory and neuroinflammation, the serotonergic system has been
studied extensively as a target for therapeutic approaches that
encompass AD and behavioral/psychological symptoms of demen-
tia (Geldenhuys et al., 2011; Rodríguez et al., 2012).
One of several mechanisms by which 5-HT may directly influ-
ence AD pathogenesis is by up-regulating a-secretase activity, via
5-HT4 receptors (Bockaert et al., 2008). Interestingly, Cirrito et al.
(2011) showed that SSRIs reduce Ab production, accumulation in
interstitial fluid and plaque deposition in a mouse model of AD
as well as in cognitively normal humans (Cirrito et al., 2011;
Sheline et al., 2014), presumably through modulation of a-
secretase activity.
As noted above, reduced 5-HT production may follow microglial
activation through increased IDO levels and activity, leading to
depressive-like symptoms. Interestingly, recent evidence suggests
Please cite this article in press as: Santos, L.E., et al. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav. Immun. (2015),
http://dx.doi.org/10.1016/j.bbi.2015.11.011
7
that changes in microglial kynurenine production may also be pre-
sent in neurodegenerative disorders (Maddison and Giorgini, 2015;
Vécsei et al., 2013). AD patients were found to have reduced levels
of plasma tryptophan and increased quinolinic acid (Gulaj et al.,
2010), as well as increased IDO immunoreactivity in hippocampal
microglia (Bonda et al., 2010). Targeting the kynurenine pathway
using inhibitors of IDO or kynurenine hydroxylase could be a
potential strategy for simultaneously treating MDD and AD, a pro-
posal that already has some support from animal studies
(O’Connor et al., 2009; Yu et al., 2015).
Yet another way by which 5-HT may be involved in MDD and
AD is by modulating hippocampal neurogenesis. In addition to its
role in MDD, detailed in a previous section, hippocampal neuroge-
nesis may be stimulated by SSRIs (Chang et al., 2012; Kim et al.,
2013). In AD, although its relevance to disease progression is not
established, neurogenesis may have compensatory roles in mem-
ory loss, as it may counter neuronal damage to some extent
(Demars et al., 2010; Jin et al., 2004; Lazarov and Marr, 2013; Mu
and Gage, 2011). IGF-1, BDNF (two factors that can be induced
by 5-HT) and 5-HT itself have all been shown to stimulate hip-
pocampal neurogenesis (Ziv and Schwartz, 2008; Ziv et al., 2006).
The relationship between these three molecules has been proposed
as central to the aging process (Mattson et al., 2004) and, given
their ties to neuroinflammation, could also underlie the links
between depression and dementia.
In this context, an interesting non-pharmacological approach
that holds promise in terms of warding off depression and demen-
tia through immunomodulation is physical exercise. Anti-
inflammatory effects of exercise were first described in the periph-
ery, being credited to altered levels of circulating cytokines, macro-
phage TLRs and reduced visceral fat (Gleeson et al., 2011). But
recent work suggests that physical exercise may modulate age-
related changes in microglia, reducing expression of pro-
inflammatory mediators and stimulating neurogenesis (Kohman
et al., 2013; Vukovic et al., 2012). Exercise was shown to favor a
neuroprotective microglial profile, with positive consequences in
animal models of aging and of depressive-like behavior (Kohman
et al., 2012; Eyre et al., 2013), as well as decreased Ab accumula-
tion in a mouse model of AD (Adlard et al., 2005).
Interestingly, using a transgenic mouse that lacks brain 5-HT,
Klempin et al. (2013) showed that serotonergic transmission is
strictly required for exercise-induced stimulation of hippocampal
neurogenesis. Those authors also noted that microglia were signif-
icantly more abundant in the hippocampi of 5-HT knockout mice
after exercise, which may be related to a lack of anti-
inflammatory 5-HT input, and may be partially responsible for
the lack of neurogenesis (Beckman and Santos, 2013). Indeed,
pro-inflammatory microglia are associated with a reduced number
of new neurons in the hippocampus, and IFN-a was shown to
directly suppress neural stem cell proliferation (Zheng et al., 2014).
Notably, a number of clinical trials have addressed the effective-
ness of facilitating 5-HT-mediated synaptic communication, by
means of SSRIs, to treat depression in patients with dementia,
but so far they have produced conflicting results (Banerjee et al.,
2011; Lyketsos et al., 2003; Nelson and Devanand, 2011; Sepehry
et al., 2012). Fewer studies, however, have focused on cognitive
performance in AD patients treated with SSRIs. Additional trials
targeting SSRIs as potential disease modifying agents appear war-
ranted to determine their potential usefulness in AD therapeutics
(Chow et al., 2007).
5.4. Ab oligomers
Ab oligomers (AbOs) are soluble forms of the Ab peptide that
accumulate in AD brains, have been shown to cause synaptic defi-
cits and memory impairment in multiple animal models, and are
8 L.E. Santos et al. / Brain, Behavior, and Immunity xxx (2015) xxx–xxx

Fig. 1. Alternative microglial activation states as potential therapeutic targets in AD and MDD. Exogenous and endogenous factors such as aging, infections, stress, brain
trauma and systemic inflammation/metabolic deregulation can induce microglial activation and contribute to CNS pathologies, including AD and MDD. Inflammatory (often
called ‘‘M1-like”) microglia show increased production and secretion of cytokines such as IL-1b, IL-6 and TNF-a, with negative consequences to cognition and increased risk of
AD (see also Heneka et al., 2015a). Inflammatory microglia also exhibit upregulated indolamine-2,3-dioxygenase (IDO), reducing serotonin availability and possibly
contributing to depression. Pharmacological or non-pharmacological approaches favoring a neuroprotective microglial phenotype (classically referred to as ‘‘M2-like”) may
promote neurogenesis, improve Ab clearance, and contribute to an overall lower level of neuroinflammation and release of neurotrophins, potentially beneficial in both AD
and MDD.

increasingly recognized as proximal neurotoxins in AD (Ferreira
et al., 2007; Ferreira and Klein, 2011). Remarkably, a single injec-
tion of AbOs (10 pmol) into the lateral cerebral ventricle causes
rapid and persistent memory impairment in mice (Figueiredo
et al., 2013). Intriguingly, we recently found that Ab oligomers
(AbOs) trigger depressive-like behavior in mice, accompanied by
brain inflammation comprising microglial/astrocyte activation
and release of the pro-inflammatory cytokines TNF-a and IL-1b,
and (Ledo et al., 2013). These findings suggest AbOs may provide
a mechanistic link between AD and MDD. Pre-treatment of mice
with fluoxetine, a commonly used SSRI, prevented both
depressive-like behavior and memory loss induced by AbO infu-
sion, and reduced microglia density and brain levels of pro-
inflammatory cytokines (Ledo et al., 2013). These results suggest
that fluoxetine itself and/or the increased availability of 5-HT could
have a relevant effect on AbO-activated microglia, simultaneously
contributing to ameliorating mood and memory in AD.
6. Conclusion
In line with a role of microglia as a link between AD and depres-
sion, an anti-inflammatory drug, minocycline, is currently going
through phase two clinical trials for both MDD (Dean et al.,
2014) and AD (The MADE trial – ISRCTN16105064). In the context
of MDD, numerous animal studies underlie the potential of
minocycline (reviewed by Carvalho et al., 2014; Dean et al.,
2012; Soczynska et al., 2012), including recent work showing it sig-
nificantly suppresses depressive-like behavior and inhibition of
neurogenesis in IFN-a-treated mice (Zheng et al., 2015). In AD,
although anti-inflammatory approaches have so far failed to block
disease progression, minocycline appears promising due to its
selective effect on microglial activation, which seems to favor
lower TNF-a and IL-1b production (Kobayashi et al., 2013) while
preserving phagocytic behavior and, possibly, Ab clearance.
AD is a complex neurodegenerative disorder, and our limited
knowledge of its pathophysiology remains an obstacle for the
development of effective therapies. Drugs currently approved for
use in AD are not disease modifying, and are useful only for symp-
tomatic management. Likewise, the mechanisms underlying MDD
are still poorly understood, and available pharmacological
approaches are not always effective or reliable (Rush et al.,
2006). In the past decade, considerable evidence has established
microglia-mediated inflammation as an important component of
both AD and MDD (Cunningham, 2013; Yirmiya et al., 2015).
Increased levels of pro-inflammatory cytokines and a shift in tryp-
tophan use towards the microglial kynurenine pathway have been
reported in AD and MDD, and have been proposed as causal factors
in both disorders (Dantzer et al., 2008; Gong et al., 2011). While a
more aggressive, pro-inflammatory microglial phenotype may be
detrimental to neurons and lead to memory impairment and mood
disturbances, alternative, more benign phenotypes may actually be
protective and increase Ab clearance/detoxification. Rebalancing
microglial responses may thus be beneficial, especially so for
comorbid AD and MDD (Fig. 1). As argued above, if the inflamma-
tion hypothesis linking AD and MDD proves valid, modulating
microglial reactivity could be more than a palliative approach.
Finally, understanding microglial priming, activation states and
age-related dysfunction may reveal relevant therapeutic targets
against dementia and virtually all brain related disorders, even
those not causally linked to inflammation.
Acknowledgments
Work in the authors’ laboratory is supported by grants from the
National Institute for Translational Neuroscience/Brazil, Conselho
Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado
do Rio de Janeiro (FAPERJ). L.E.S. and D.B. are pre-doctoral fellows
supported by CNPq.
References
Aarum, J., Sandberg, K., Haeberlein, S.L.B., Persson, M.A.A., 2003. Migration and
differentiation of neural precursor cells can be directed by microglia. Proc. Natl.

Please cite this article in press as: Santos, L.E., et al. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav. Immun. (2015),
http://dx.doi.org/10.1016/j.bbi.2015.11.011
 L.E. Santos et al. / Brain, Behavior, and Immunity xxx (2015) xxx–xxx
Acad. Sci. U.S.A. 100, 15983–15988. http://dx.doi.org/10.1073/
pnas.2237050100.
Adlard, P.A., Perreau, V.M., Pop, V., Cotman, C.W., 2005. Voluntary exercise
decreases amyloid load in a transgenic model of Alzheimer’s disease. J.
Neurosci. 25, 4217–4221. http://dx.doi.org/10.1523/JNEUROSCI.0496-05.2005.
Ajami, B., Bennett, J.L., Krieger, C., Tetzlaff, W., Rossi, F.M.V., 2007. Local self-renewal
can sustain CNS microglia maintenance and function throughout adult life. Nat.
Neurosci. 10, 1538–1543. http://dx.doi.org/10.1038/nn2014.
Akhondzadeh, S., Jafari, S., Raisi, F., Nasehi, A.A., Ghoreishi, A., Salehi, B., Mohebbi-
Rasa, S., Raznahan, M., Kamalipour, A., 2009. Clinical trial of adjunctive
celecoxib treatment in patients with major depression: a double blind and
placebo controlled trial. Depress. Anxiety 26, 607–611. http://dx.doi.org/
10.1002/da.20589.
Alesci, S., Martinez, P.E., Kelkar, S., Ilias, I., Ronsaville, D.S., Listwak, S.J., Ayala, A.R.,
Licinio, J., Gold, H.K., Kling, M.A., Chrousos, G.P., Gold, P.W., 2005. Major
depression is associated with significant diurnal elevations in plasma
interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological
complexity in its secretion: clinical implications. J. Clin. Endocrinol. Metab. 90,
2522–2530. http://dx.doi.org/10.1210/jc.2004-1667.
Allegri, R.F., Sarasola, D., Serrano, C.M., Taragano, F.E., Arizaga, R.L., Butman, J., Loñ,
L., 2006. Neuropsychiatric symptoms as a predictor of caregiver burden in
Alzheimer’s disease. Neuropsychiatr. Dis. Treat. 2, 105–110.
Álvarez, A., Cacabelos, R., Sanpedro, C., García-Fantini, M., Aleixandre, M., 2007.
Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in
Alzheimer disease. Neurobiol. Aging 28, 533–536. http://dx.doi.org/10.1016/j.
neurobiolaging.2006.02.012.
Anisman, H., Hayley, S., 2012. Inflammatory factors contribute to depression and its
comorbid conditions. Sci. Signal. 5. http://dx.doi.org/10.1126/
scisignal.2003579, pe45–pe45.
Apostolova, L.G., Cummings, J.L., 2008. Neuropsychiatric manifestations in mild
cognitive impairment: a systematic review of the literature. Dement. Geriatr.
Cogn. Disord. 25, 115–126, 000112509 [pii] 10.1159/000112509.
Baalman, K., Marin, M.A., Ho, T.S.-Y., Godoy, M., Cherian, L., Robertson, C., Rasband,
M.N., 2015. Axon initial segment-associated microglia. J. Neurosci. 35, 2283–
2292. http://dx.doi.org/10.1523/JNEUROSCI.3751-14.2015.
Banerjee, S., Hellier, J., Dewey, M., Romeo, R., Ballard, C., Baldwin, R., Bentham, P.,
Fox, C., Holmes, C., Katona, C., Knapp, M., Lawton, C., Lindesay, J., Livingston, G.,
McCrae, N., Moniz-Cook, E., Murray, J., Nurock, S., Orrell, M., O’Brien, J., Poppe,
M., Thomas, A., Walwyn, R., Wilson, K., Burns, A., 2011. Sertraline or mirtazapine
for depression in dementia (HTA-SADD): a randomised, multicentre, double-
blind, placebo-controlled trial. Lancet 378, 403–411. http://dx.doi.org/10.1016/
S0140-6736(11)60830-1.
Barnabé-Heider, F., Miller, F.D., 2003. Endogenously produced neurotrophins
regulate survival and differentiation of cortical progenitors via distinct
signaling pathways. J. Neurosci. 23, 5149–5160.
Beckman, D., Santos, L.E., 2013. The importance of serotonin in exercise-induced
adult neurogenesis: new evidence from Tph2/ mice. J. Neurosci. 33, 14283–
14284. http://dx.doi.org/10.1523/JNEUROSCI.2911-13.2013.
Benoit, M., Berrut, G., Doussaint, J., Bakchine, S., Bonin-Guillaume, S., Frémont, P.,
Gallarda, T., Krolak-Salmon, P., Marquet, T., Mékiès, C., Sellal, F., Schuck, S.,
David, R., Robert, P., 2012. Apathy and depression in mild Alzheimer’s disease: a
cross-sectional study using diagnostic criteria. J. Alzheimers. Dis. 31, 325–334.
http://dx.doi.org/10.3233/JAD-2012-112003.
Berton, O., Nestler, E.J., 2006. New approaches to antidepressant drug discovery:
beyond monoamines. Nat. Rev. Neurosci. 7, 137–151. http://dx.doi.org/10.1038/
nrn1846.
Bluthé, R.-M., Kelley, K.W., Dantzer, R., 2006. Effects of insulin-like growth factor-I
on cytokine-induced sickness behavior in mice. Brain Behav. Immun. 20, 57–63.
http://dx.doi.org/10.1016/j.bbi.2005.02.003.
Bocchio-Chiavetto, L., Bagnardi, V., Zanardini, R., Molteni, R., Nielsen, M.G.,
Placentino, A., Giovannini, C., Rillosi, L., Ventriglia, M., Riva, M.A., Gennarelli,
M., 2010. Serum and plasma BDNF levels in major depression: a replication
study and meta-analyses. World J. Biol. Psychiatry 11, 763–773. http://dx.doi.
org/10.3109/15622971003611319.
Bockaert, J., Claeysen, S., Compan, V., Dumuis, A., 2008. 5-HT4 receptors: history,
molecular pharmacology and brain functions. Neuropharmacology 55, 922–
931. http://dx.doi.org/10.1016/j.neuropharm.2008.05.013.
Boldrini, M., Hen, R., Underwood, M.D., Rosoklija, G.B., Dwork, A.J., Mann, J.J.,
Arango, V., 2012. Hippocampal angiogenesis and progenitor cell proliferation
are increased with antidepressant use in major depression. Biol. Psychiatry 72,
562–571. http://dx.doi.org/10.1016/j.biopsych.2012.04.024.
Boldrini, M., Santiago, A.N., Hen, R., Dwork, A.J., Rosoklija, G.B., Tamir, H., Arango, V.,
John Mann, J., 2013. Hippocampal granule neuron number and dentate gyrus
volume in antidepressant-treated and untreated major depression.
Neuropsychopharmacology 38, 1068–1077. http://dx.doi.org/10.1038/
npp.2013.5.
Bomfim, T.R., Forny-Germano, L., Sathler, L.B., Brito-Moreira, J., Houzel, J.C., Decker,
H., Silverman, M.A., Kazi, H., Melo, H.M., McClean, P.L., Holscher, C., Arnold, S.E.,
Talbot, K., Klein, W.L., Munoz, D.P., Ferreira, S.T., De Felice, F.G., 2012. An anti-
diabetes agent protects the mouse brain from defective insulin signaling caused
by Alzheimer’s disease-associated Ab oligomers. J. Clin. Invest. 122, 1339–1353.
http://dx.doi.org/10.1172/JCI57256.
Bonda, D.J., Mailankot, M., Stone, J.G., Garrett, M.R., Staniszewska, M., Castellani, R.J.,
Siedlak, S.L., Zhu, X., Lee, H., Perry, G., Nagaraj, R.H., Smith, M.A., 2010.
Indoleamine 2,3-dioxygenase and 3-hydroxykynurenine modifications are
Please cite this article in press as: Santos, L.E., et al. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav. Immun. (2015),
http://dx.doi.org/10.1016/j.bbi.2015.11.011
9
found in the neuropathology of Alzheimer’s disease. Redox Rep. 15, 161–168.
http://dx.doi.org/10.1179/174329210X12650506623645.
Bremner, J.D., Narayan, M., Anderson, E.R., Staib, L.H., Miller, H.L., Charney, D.S.,
2000. Hippocampal volume reduction in major depression. Am. J. Psychiatry
157, 115–118. http://dx.doi.org/10.1176/appi.ajp.157.1.115.
Bufalino, C., Hepgul, N., Aguglia, E., Pariante, C.M., 2013. The role of immune genes
in the association between depression and inflammation: a review of recent
clinical studies. Brain Behav. Immun. 31, 31–47. http://dx.doi.org/10.1016/j.
bbi.2012.04.009.
Burns, A., Jacoby, R., Levy, R., 1990a. Psychiatric phenomena in Alzheimer’s disease.
III. Disorders of mood. Br. J. Psychiatry 157, 81–86. http://dx.doi.org/10.1192/
bjp.157.1.81.
Burns, A., Jacoby, R., Levy, R., 1990b. Psychiatric phenomena in Alzheimer’s disease.
IV. Disorders of behaviour. Br. J. Psychiatry 157, 86–94. http://dx.doi.org/
10.1192/bjp.157.1.86.
Butters, M.A., Young, J.B., Lopez, O., Aizenstein, H.J., Mulsant, B.H., Reynolds, C.F.,
DeKosky, S.T., Becker, J.T., 2008. Pathways linking late-life depression to
persistent cognitive impairment and dementia. Dialogues Clin. Neurosci. 10,
345–357. http://dx.doi.org/10.1016/j.bbi.2008.05.010.
Cannon, J.P., O’Driscoll, M., Litman, G.W., 2012. Specific lipid recognition is a general
feature of CD300 and TREM molecules. Immunogenetics 64, 39–47. http://dx.
doi.org/10.1007/s00251-011-0562-4.
Carro, E., Torres-Aleman, I., 2004. Insulin-like growth factor I and Alzheimer’s
disease: therapeutic prospects? Expert Rev. Neurother. 4, 79–86. http://dx.doi.
org/10.1586/14737175.4.1.79.
Carro, E., Trejo, J.L., Gomez-Isla, T., LeRoith, D., Torres-Aleman, I., 2002. Serum
insulin-like growth factor I regulates brain amyloid-beta levels. Nat. Med. 8,
1390–1397. http://dx.doi.org/10.1038/nm793.
Carvalho, A.F., Miskowiak, K.K., Hyphantis, T.N., Köhler, C.A., Alves, G.S., Bortolato,
B., Sales, P.M.G., Machado-vieira, R., Berk, M., Mcintyre, R.S., 2014. Cognitive
dysfunction in depression – pathophysiology and novel targets. CNS Neurol.
Disord.: Drug Targets 13, 1819–1835.
Casano, A.M., Peri, F., 2015. Microglia: multitasking specialists of the brain. Dev. Cell
32, 469–477. http://dx.doi.org/10.1016/j.devcel.2015.01.018.
Cassilhas, R.C., Antunes, H.K.M., Tufik, S., de Mello, M.T., 2010. Mood, anxiety, and
serum IGF-1 in elderly men given 24 weeks of high resistance exercise. Percept.
Mot. Skills 110, 265–276. http://dx.doi.org/10.2466/PMS.110.1.265-276.
Chakrabarty, P., Li, A., Das, P., Golde, T.E., Chakrabarty, P., Li, A., Ceballos-diaz, C.,
Eddy, J.A., Funk, C.C., Moore, B., Dinunno, N., Rosario, A.M., Cruz, P.E., Verbeeck,
C., Sacino, A., Nix, S., 2015. IL-10 alters immunoproteostasis in APP mice,
increasing plaque burden and worsening cognitive article IL-10 alters
immunoproteostasis in APP Mice, increasing plaque burden and worsening
cognitive behavior. Neuron 85, 519–533. http://dx.doi.org/10.1016/j.
neuron.2014.11.020.
Chang, K.A., Kim, J.A., Kim, S.S., Joo, Y., Shin, K.Y., Kim, S.S., Kim, H.S., Suh, Y.H., 2012.
Therapeutic potentials of neural stem cells treated with fluoxetine in
Alzheimer’s disease. Neurochem. Int. 61, 885–891. http://dx.doi.org/10.1016/j.
neuint.2012.03.017.
Chemerinski, E., Petracca, G., Sabe, L., Kremer, J., Starkstein, S.E., 2001. The
specificity of depressive symptoms in patients with Alzheimer’s disease. Am.
J. Psychiatry 158, 68–72. http://dx.doi.org/10.1176/appi.ajp.158.1.68.
Chen, Z., Trapp, B.D., 2015. Microglia and neuroprotection. J. Neurochem. 1–8.
http://dx.doi.org/10.1111/jnc.13062.
Chen, S.Y., Chen, T.F., Lai, L.C., Chen, J.H., Sun, Y., Wen, L.L., Yip, P.K., Chu, Y.M., Chen,
Y.C., 2012. Sequence variants of interleukin 6 (IL-6) are significantly associated
with a decreased risk of late-onset Alzheimer’s disease. J. Neuroinflamm. 9, 21.
http://dx.doi.org/10.1186/1742-2094-9-21.
Cherry, J.D., Olschowka, J.A., O’Banion, M.K., 2014. Neuroinflammation and M2
microglia: the good, the bad, and the inflamed. J. Neuroinflamm. 11, 98. http://
dx.doi.org/10.1186/1742-2094-11-98.
Chi, S., Yu, J.-T., Tan, M.-S., Tan, L., 2014. Depression in Alzheimer’s disease:
epidemiology, mechanisms, and management. J. Alzheimers. Dis. 42, 739–755.
http://dx.doi.org/10.3233/JAD-140324.
Chi, S., Wang, C., Jiang, T., Zhu, X.-C., Yu, J.-T., Tan, L., 2015. The prevalence of
depression in Alzheimer’s disease: a systematic review and meta-analysis. Curr.
Alzheimer Res. 12, 189–198.
Choi, S., Li, Y., Parada, L.F., Sisodia, S.S., 2009. Regulation of hippocampal progenitor
cell survival, proliferation and dendritic development by BDNF. Mol.
Neurodegener. 4, 52. http://dx.doi.org/10.1186/1750-1326-4-52.
Chow, T.W., Pollock, B.G., Milgram, N.W., 2007. Potential cognitive enhancing and
disease modification effects of SSRIs for Alzheimer’s disease. Neuropsychiatr.
Dis. Treat. 3, 627–636.
Cirrito, J.R., Disabato, B.M., Restivo, J.L., Verges, D.K., Goebel, W.D., Sathyan, A.,
Hayreh, D., D’Angelo, G., Benzinger, T., Yoon, H., Kim, J., Morris, J.C., Mintun, M.
A., Sheline, Y.I., 2011. Serotonin signaling is associated with lower amyloid-
{beta} levels and plaques in transgenic mice and humans. Proc. Natl. Acad. Sci.
U.S.A. 108, 14968–14973. http://dx.doi.org/10.1073/pnas.1107411108.
Clark, C.M., Schneider, J.A., Bedell, B.J., Beach, T.G., Bilker, W.B., Mintun, M.A.,
Pontecorvo, M.J., Hefti, F., Carpenter, A.P., Flitter, M.L., Krautkramer, M.J., Kung,
H.F., Coleman, R.E., Doraiswamy, P.M., Fleisher, A.S., Sabbagh, M.N., Sadowsky,
C.H., Reiman, E.P., Zehntner, S.P., Skovronsky, D.M., 2011. Use of florbetapir-PET
for imaging beta-amyloid pathology. JAMA 305, 275–283. http://dx.doi.org/
10.1001/jama.2010.2008.
Colonna, M., 2003. TREMs in the immune system and beyond. Nat. Rev. Immunol. 3,
445–453. http://dx.doi.org/10.1038/nri1106.
10 L.E. Santos et al. / Brain, Behavior, and Immunity xxx (2015) xxx–xxx
Condello, C., Yuan, P., Schain, A., Grutzendler, J., 2015. Microglia constitute a barrier
that prevents neurotoxic protofibrillar Ab42 hotspots around plaques. Nat.
Commun. 6, 6176. http://dx.doi.org/10.1038/ncomms7176.
Coppen, A., 1967. The biochemistry of affective disorders. Br. J. Psychiatry 113,
1237–1264. http://dx.doi.org/10.1192/bjp.113.504.1237.
Cummings, J.L., Mega, M., Gray, K., Rosenberg-Thompson, S., Carusi, D.A., Gornbein,
J., 1994. The neuropsychiatric inventory: comprehensive assessment of
psychopathology in dementia. Neurology 44, 2308–2314. http://dx.doi.org/
10.1212/WNL.44.12.2308.
Cunningham, C., 2013. Microglia and neurodegeneration: the role of systemic
inflammation. Glia 61, 71–90. http://dx.doi.org/10.1002/glia.22350.
Curtis, C., Gamez, J.E., Singh, U., Al, E., 2015. Phase 3 trial of flutemetamol labeled
with radioactive fluorine 18 imaging and neuritic plaque density. JAMA Neurol.
72, 287–294.
Dai, L., Liu, D., Guo, H., Wang, Y., Bai, Y., 2012. Association between polymorphism in
the promoter region of Interleukin 6 (-174 G/C) and risk of Alzheimer’s disease:
a meta-analysis. J. Neurol. 259, 414–419. http://dx.doi.org/10.1007/s00415-
011-6164-0.
Dantzer, R., Walker, A.K., 2014. Is there a role for glutamate-mediated excitotoxicity
in inflammation-induced depression? J. Neural Transm. 925–932. http://dx.doi.
org/10.1007/s00702-014-1187-1.
Dantzer, R., Gheusi, G., Johnson, R.W., Kelley, K.W., 1999. Central administration of
insulin-like growth factor-1 inhibits lipopolysaccharide-induced sickness
behavior in mice. NeuroReport 10, 289–292.
Dantzer, R., O’Connor, J.C., Freund, G.G., Johnson, R.W., Kelley, K.W., 2008. From
inflammation to sickness and depression: when the immune system subjugates
the brain. Nat. Rev. Neurosci. 9, 46–56. http://dx.doi.org/10.1038/nrn2297.
De Felice, F.G., 2013. Alzheimer’s disease and insulin resistance: translating basic
science into clinical applications. J. Clin. Invest. 123, 531–539. http://dx.doi.org/
10.1172/JCI64595.
De Felice, F.G., Ferreira, S.T., 2014. Inflammation, defective insulin signaling, and
mitochondrial dysfunction as common molecular denominators connecting
type 2 diabetes to Alzheimer disease. Diabetes 63, 2262–2272. http://dx.doi.
org/10.2337/db13-1954.
De Felice, F.G., Lourenco, M.V., Ferreira, S.T., 2014. How does brain insulin resistance
develop in Alzheimer’s disease? Alzheimer’s Dement. 10, S26–S32. http://dx.
doi.org/10.1016/j.jalz.2013.12.004.
Dean, O.M., Data-Franco, J., Giorlando, F., Berk, M., 2012. Minocycline: therapeutic
potential in psychiatry. CNS Drugs 26, 391–401. http://dx.doi.org/10.2165/
11632000-000000000-00000.
Dean, O.M., Maes, M., Ashton, M., Berk, L., Kanchanatawan, B., Sughondhabirom, A.,
Tangwongchai, S., Ng, C., Dowling, N., Malhi, G.S., Berk, Mi., 2014. Protocol and
rationale-the efficacy of minocycline as an adjunctive treatment for major
depressive disorder: a double blind, randomised, placebo controlled trial. Clin.
Psychopharmacol. Neurosci. 12, 180–188. http://dx.doi.org/10.9758/
cpn.2014.12.3.180.
Demars, M., Hu, Y.-S., Gadadhar, A., Lazarov, O., 2010. Impaired neurogenesis is an
early event in the etiology of familial Alzheimer’s disease in transgenic mice. J.
Neurosci. Res. 88, 2103–2117. http://dx.doi.org/10.1002/jnr.22387.
Denicoff, K.D., Rubinow, D.R., Papa, M.Z., Simpson, C., Seipp, C.A., Lotze, M.T., Chang,
A.E., Rosenstein, D., Rosenberg, S.A., 1987. The neuropsychiatric effects of
treatment with interleukin-2 and lymphokine-activated killer cells. Ann. Intern.
Med. 107, 293–300.
Doecke, J.D., Laws, S.M., Faux, N.G., Wilson, W., Burnham, S.C., Lam, C.-P., Mondal, A.,
Bedo, J., Bush, A.I., Brown, B., De Ruyck, K., Ellis, K.A., Fowler, C., Gupta, V.B.,
Head, R., Macaulay, S.L., Pertile, K., Rowe, C.C., Rembach, A., Rodrigues, M.,
Rumble, R., Szoeke, C., Taddei, K., Taddei, T., Trounson, B., Ames, D., Masters, C.L.,
Martins, R.N., 2012. Blood-based protein biomarkers for diagnosis of Alzheimer
disease. Arch. Neurol. 69, 1318–1325. http://dx.doi.org/10.1001/
archneurol.2012.1282.
Doens, D., Fernández, P.L., 2014. Microglia receptors and their implications in the
response to amyloid b for Alzheimer’s disease pathogenesis. J. Neuroinflamm.
11, 48. http://dx.doi.org/10.1186/1742-2094-11-48.
Dougherty, K.D., Dreyfus, C.F., Black, I.B., 2000. Brain-derived neurotrophic factor in
astrocytes, oligodendrocytes, and microglia/macrophages after spinal cord
injury. Neurobiol. Dis. 7, 574–585. http://dx.doi.org/10.1006/nbdi.2000.0318.
Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E.K., Lanctôt, K.L.,
2010. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67,
446–457. http://dx.doi.org/10.1016/j.biopsych.2009.09.033.
Dunger, D.B., Ong, K.K.L., Sandhu, M.S., 2003. Serum insulin-like growth factor-I
levels and potential risk of type 2 diabetes. Horm. Res. 60 (Suppl. 3), 131–135.
http://dx.doi.org/10.1159/000074514.
Dwivedi, Y., 2013. Involvement of brain-derived neurotrophic factor in late-life
depression. Am. J. Geriatr. Psychiatry 21, 433–449. http://dx.doi.org/10.1016/
j.jagp.2012.10.026.
Ekdahl, C.T., Claasen, J.-H., Bonde, S., Kokaia, Z., Lindvall, O., 2003. Inflammation is
detrimental for neurogenesis in adult brain. Proc. Natl. Acad. Sci. U.S.A. 100,
13632–13637. http://dx.doi.org/10.1073/pnas.2234031100.
El Khoury, J., Toft, M., Hickman, S.E., Means, T.K., Terada, K., Geula, C., Luster, A.D.,
2007. Ccr2 deficiency impairs microglial accumulation and accelerates
progression of Alzheimer-like disease. Nat. Med. 13, 432–438. http://dx.doi.
org/10.1038/nm1555.
Eriksson, P.S., Perfilieva, E., Björk-Eriksson, T., Alborn, A.M., Nordborg, C., Peterson,
D.A., Gage, F.H., 1998. Neurogenesis in the adult human hippocampus. Nat.
Med. 4, 1313–1317. http://dx.doi.org/10.1038/3305.
Please cite this article in press as: Santos, L.E., et al. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav. Immun. (2015),
http://dx.doi.org/10.1016/j.bbi.2015.11.011
Eyre, H.A., Papps, E., Baune, B.T., 2013. Treating Depression and Depression-Like
Behavior with Physical Activity: An Immune Perspective. Front. Psychiatry 4, 1–
27. http://dx.doi.org/10.3389/fpsyt.2013.00003.
Felger, J.C., Lotrich, F.E., 2013. Inflammatory cytokines in depression:
neurobiological mechanisms and therapeutic implications. Neuroscience 246,
199–229. http://dx.doi.org/10.1016/j.neuroscience.2013.04.060.
Fenn, A.M., Hall, J.C.E., Gensel, J.C., Popovich, P.G., Godbout, J.P., 2014. IL-4 signaling
drives a unique arginase+/IL-1+ microglia phenotype and recruits macrophages
to the inflammatory CNS: consequences of age-related deficits in IL-4R after
traumatic spinal cord injury. J. Neurosci. 34, 8904–8917. http://dx.doi.org/
10.1523/JNEUROSCI.1146-14.2014.
Ferreira, S.T., Klein, W.L., 2011. The Ab oligomer hypothesis for synapse failure and
memory loss in Alzheimer’s disease. Neurobiol. Learn. Mem. 96, 529–543.
http://dx.doi.org/10.1016/j.nlm.2011.08.003.
Ferreira, S.T., Vieira, M.N.N., De Felice, F.G., 2007. Soluble protein oligomers as
emerging toxins in Alzheimer’s and other amyloid diseases. IUBMB Life 59,
332–345. http://dx.doi.org/10.1080/15216540701283882.
Ferreira, S.T., Clarke, J.R., Bomfim, T.R., De Felice, F.G., 2014. Inflammation,
defective insulin signaling, and neuronal dysfunction in Alzheimer’s
disease. Alzheimer’s Dement. 10, S76–S83. http://dx.doi.org/10.1016/
j.jalz.2013.12.010.
Figueiredo, C.P., Clarke, J.R., Ledo, J.H., Ribeiro, F.C., Costa, C.V., Melo, H.M., Mota-
Sales, A.P., Saraiva, L.M., Klein, W.L., Sebollela, A., De Felice, F.G., Ferreira, S.T.,
2013. Memantine rescues transient cognitive impairment caused by high-
molecular-weight ab oligomers but not the persistent impairment induced by
low-molecular-weight oligomers. J. Neurosci. 33, 9626–9634. http://dx.doi.org/
10.1523/JNEUROSCI.0482-13.2013.
Fiske, A., Wetherell, J.L., Gatz, M., 2009. Depression in older adults. Annu. Rev. Clin.
Psychol. 5, 363–389. http://dx.doi.org/10.1146/
annurev.clinpsy.032408.153621.
Frank, S., Burbach, G.J., Bonin, M., Walter, M., Streit, W., Bechmann, I., Deller, T.,
2008. TREM2 is upregulated in amyloid plaque-associated microglia in aged
APP23 transgenic mice. Glia 56, 1438–1447. http://dx.doi.org/10.1002/
glia.20710.
Gauthier, S., Reisberg, B., Zaudig, M., Petersen, R.C., Ritchie, K., Broich, K., Belleville,
S., Brodaty, H., Bennett, D., Chertkow, H., Cummings, J.L., de Leon, M., Feldman,
H., Ganguli, M., Hampel, H., Scheltens, P., Tierney, M.C., Whitehouse, P.,
Winblad, B., 2006. Mild cognitive impairment. Lancet 367, 1262–1270. http://
dx.doi.org/10.1016/S0140-6736(06)68542-5.
Geldenhuys, W.J., der Schyf, C.J., Van Der Schyf, C.J., der Schyf, C.J., 2011. Role of
serotonin in Alzheimer’s disease: a new therapeutic target? CNS Drugs 25, 765–
781. http://dx.doi.org/10.2165/11590190-000000000-00000.
Gemma, C., Bachstetter, A.D., 2013. The role of microglia in adult hippocampal
neurogenesis. Front. Cell. Neurosci. 7, 229. http://dx.doi.org/10.3389/
fncel.2013.00229.
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M.F.,
Conway, S.J., Ng, L.G., Stanley, E.R., Samokhvalov, I.M., Merad, M., 2010. Fate
mapping analysis reveals that adult microglia derive from primitive
macrophages. Science 330, 841–845. http://dx.doi.org/
10.1126/science.1194637.
Glebov, K., Löchner, M., Jabs, R., Lau, T., Merkel, O., Schloss, P., Steinhäuser, C.,
Walter, J., 2015. Serotonin stimulates secretion of exosomes from microglia
cells. Glia 63, 626–634. http://dx.doi.org/10.1002/glia.22772.
Gleeson, M., Bishop, N.C., Stensel, D.J., Lindley, M.R., Mastana, S.S., Nimmo, M.A.,
2011. The anti-inflammatory effects of exercise: mechanisms and implications
for the prevention and treatment of disease. Nat. Rev. Immunol. 11, 607–615.
http://dx.doi.org/10.1038/nri3041.
Gong, C.Y., Li, Z., Wang, H.M., Liu, J., Chen, L., Zhang, H.W., Wang, X., Yang, J., 2011.
Targeting the kynurenine pathway as a potential strategy to prevent and treat
Alzheimer’s disease. Med. Hypotheses 77, 383–385. http://dx.doi.org/10.1016/j.
mehy.2011.05.022.
Grassi-Oliveira, R., Brietzke, E., Pezzi, J.C., Lopes, R.P., Teixeira, A.L., Bauer, M.E., 2009.
Increased soluble tumor necrosis factor-alpha receptors in patients with major
depressive disorder. Psychiatry Clin. Neurosci. 63, 202–208. http://dx.doi.org/
10.1111/j.1440-1819.2008.01918.x.
Green, R.C., Cupples, L.A., Kurz, A., Auerbach, S., Go, R., Sadovnick, D., Duara, R.,
Kukull, W.A., Chui, H., Edeki, T., Griffith, P.A., Friedland, R.P., Bachman, D., Farrer,
L., 2003. Depression as a risk factor for Alzheimer disease: the MIRAGE Study.
Arch. Neurol. 60, 753–759. http://dx.doi.org/10.1001/archneur.60.5.753.
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E.,
Cruchaga, C., Sassi, C., Kauwe, J.S.K., Younkin, S., Hazrati, L., Collinge, J., Pocock, J.,
Lashley, T., Williams, J., Lambert, J.-C., Amouyel, P., Goate, A., Rademakers, R.,
Morgan, K., Powell, J., St George-Hyslop, P., Singleton, A., Hardy, J., 2013. TREM2
variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127. http://dx.doi.org/
10.1056/NEJMoa1211851.
Guillot-Sestier, M.V., Doty, K.R., Gate, D., Rodriguez, J., Leung, B.P., Rezai-Zadeh, K.,
Town, T., 2015. Il10 deficiency rebalances innate immunity to mitigate
Alzheimer-like pathology article Il10 deficiency rebalances innate immunity
to mitigate Alzheimer-like pathology. Neuron 85, 1–15. http://dx.doi.org/
10.1016/j.neuron.2014.12.068.
Gulaj, E., Pawlak, K., Bien, B., Pawlak, D., 2010. Kynurenine and its metabolites in
Alzheimer’s disease patients. Adv. Med. Sci. 55, 204–211. http://dx.doi.org/
10.2478/v10039-010-0023-6.
Hart, B., 1988. Biological basis of the behavior of sick animals. Neurosci. Biobehav.
Rev. 12, 123–137.
 L.E. Santos et al. / Brain, Behavior, and Immunity xxx (2015) xxx–xxx
Hauser, P.S., Ryan, R.O., 2013. Impact of apolipoprotein E on Alzheimer’s disease.
Curr. Alzheimer Res. 10, 809–817. http://dx.doi.org/10.2174/
15672050113109990156.
Hellwig, S., Heinrich, A., Biber, K., 2013. The brain’s best friend: microglial
neurotoxicity revisited. Front. Cell. Neurosci. 7, 71. http://dx.doi.org/10.3389/
fncel.2013.00071.
Heneka, M.T., Kummer, M.P., Latz, E., 2014. Innate immune activation in
neurodegenerative disease. Nat. Rev. Immunol. 14, 463–477. http://dx.doi.org/
10.1038/nri3705.
Heneka, M.T., Carson, M.J., Khoury, J. .El., Landreth, G.E., Brosseron, F., Feinstein, D.L.,
Jacobs, A.H., Wyss-Coray, T., Vitorica, J., Ransohoff, R.M., Herrup, K., Frautschy, S.
A., Finsen, B., Brown, G.C., Verkhratsky, A., Yamanaka, K., Koistinaho, J., Latz, E.,
Halle, A., Petzold, G.C., Town, T., Morgan, D., Shinohara, M.L., Perry, V.H.,
Holmes, C., Bazan, N.G., Brooks, D.J., Hunot, S., Joseph, B., Deigendesch, N.,
Garaschuk, O., Boddeke, E., Dinarello, C.A., Breitner, J.C., Cole, G.M., Golenbock,
D.T., Kummer, M.P., 2015a. Neuroinflammation in Alzheimer’s disease. Lancet
Neurol. 14, 388–405. http://dx.doi.org/10.1016/S1474-4422(15)70016-5.
Heneka, M.T., Golenbock, D.T., Latz, E., 2015b. Innate immunity in Alzheimer’s
disease. Nat. Immunol. 16, 229–236. http://dx.doi.org/10.1038/ni.3102.
Hickman, S.E., Allison, E.K., El Khoury, J., 2008. Microglial dysfunction and defective
beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J.
Neurosci. 28, 8354–8360. http://dx.doi.org/10.1523/JNEUROSCI.0616-08.2008.
Holmes, C., Cunningham, C., Zotova, E., Woolford, J., Dean, C., Kerr, S., Culliford, D.,
Perry, V.H., 2009. Systemic inflammation and disease progression in Alzheimer
disease. Neurology 73, 768–774. http://dx.doi.org/10.1212/
WNL.0b013e3181b6bb95.
Holsinger, R.M., Schnarr, J., Henry, P., Castelo, V.T., Fahnestock, M., 2000.
Quantitation of BDNF mRNA in human parietal cortex by competitive reverse
transcription-polymerase chain reaction: decreased levels in Alzheimer’s
disease. Brain Res. Mol. Brain Res. 76, 347–354.
Holthoff, V.A., Beuthien-Baumann, B., Kalbe, E., Lüdecke, S., Lenz, O., Zündorf, G.,
Spirling, S., Schierz, K., Winiecki, P., Sorbi, S., Herholz, K., 2005. Regional cerebral
metabolism in early Alzheimer’s disease with clinically significant apathy or
depression. Biol. Psychiatry 57, 412–421. http://dx.doi.org/10.1016/j.
biopsych.2004.11.035.
Holtzheimer, P.E., Mayberg, H.S., 2011. Stuck in a rut: rethinking depression and its
treatment. Trends Neurosci. 34, 1–9. http://dx.doi.org/10.1016/j.
tins.2010.10.004.
Hoshaw, B.A., Hill, T.I., Crowley, J.J., Malberg, J.E., Khawaja, X., Rosenzweig-Lipson, S.,
Schechter, L.E., Lucki, I., 2008. Antidepressant-like behavioral effects of IGF-I
produced by enhanced serotonin transmission. Eur. J. Pharmacol. 594, 109–116.
http://dx.doi.org/10.1016/j.ejphar.2008.07.023.
Hsieh, C.L., Koike, M., Spusta, S.C., Niemi, E.C., Yenari, M., Nakamura, M.C., Seaman,
W.E., 2009. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal
cells by microglia. J. Neurochem. 109, 1144–1156. http://dx.doi.org/10.1111/
j.1471-4159.2009.06042.x.
Hu, X., Leak, R.K., Shi, Y., Suenaga, J., Gao, Y., Zheng, P., Chen, J., 2014. Microglial and
macrophage polarization—new prospects for brain repair. Nat. Rev. Neurol. 11,
56–64. http://dx.doi.org/10.1038/nrneurol.2014.207.
Hurt, C., Bhattacharyya, S., Burns, A., Camus, V., Liperoti, R., Marriott, A., Nobili, F.,
Robert, P., Tsolaki, M., Vellas, B., Verhey, F., Byrne, E.J., 2008. Patient and
caregiver perspectives of quality of life in dementia: an investigation of the
relationship to behavioural and psychological symptoms in dementia. Dement.
Geriatr. Cogn. Disord. 26, 138–146. http://dx.doi.org/10.1159/000149584.
Irwin, M.R., Miller, A.H., 2007. Depressive disorders and immunity: 20 years of
progress and discovery. Brain Behav. Immun. 21, 374–383. http://dx.doi.org/
10.1016/j.bbi.2007.01.010.
Jacobs, B.L., van Praag, H., Gage, F.H., 2000. Adult brain neurogenesis and psychiatry:
a novel theory of depression. Mol. Psychiatry 5, 262–269. http://dx.doi.org/
10.1038/sj.mp.4000712.
Janzing, J.G.E., Hooijer, C., Van ’T Hof, M.A., Zitman, F.G., 2002. Depression in
subjects with and without dementia: a comparison using GMS-AGECAT. Int. J.
Geriatr. Psychiatry 17, 1–5. http://dx.doi.org/10.1002/gps.526.
Jay, T.R., Miller, C.M., Cheng, P.J., Graham, L.C., Bemiller, S., Broihier, M.L., Xu, G.,
Margevicius, D., Karlo, J.C., Sousa, G.L., Cotleur, A.C., Butovsky, O., Bekris, L.,
Staugaitis, S.M., Leverenz, J.B., Pimplikar, S.W., Landreth, G.E., Howell, G.R.,
Ransohoff, R.M., Lamb, B.T., 2015. TREM2 deficiency eliminates TREM2+
inflammatory macrophages and ameliorates pathology in Alzheimer’s disease
mouse models. J. Exp. Med. 212, 287–295. http://dx.doi.org/
10.1084/jem.20142322.
Jin, K., Peel, A.L., Mao, X.O., Xie, L., Cottrell, B.A., Henshall, D.C., Greenberg, D.A.,
2004. Increased hippocampal neurogenesis in Alzheimer’s disease. Proc. Natl.
Acad. Sci. U.S.A. 101, 343–347. http://dx.doi.org/10.1073/pnas.2634794100.
Johansson, J.U., Woodling, N.S., Wang, Q., Panchal, M., Liang, X., Trueba-Saiz, A.,
Brown, H.D., Mhatre, S.D., Loui, T., Andreasson, K.I., 2014. Prostaglandin
signaling suppresses beneficial microglial function in Alzheimer’s
disease models. J. Clin. Invest. 125, 350–364. http://dx.doi.org/10.1172/
JCI77487.
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P.V., Snaedal, J.,
Bjornsson, S., Huttenlocher, J., Levey, A.I., Lah, J.J., Rujescu, D., Hampel, H.,
Giegling, I., Andreassen, O.A., Engedal, K., Ulstein, I., Djurovic, S., Ibrahim-
Verbaas, C., Hofman, A., Ikram, M.A., van Duijn, C.M., Thorsteinsdottir, U., Kong,
A., Stefansson, K., 2013. Variant of TREM2 associated with the risk of
Alzheimer’s disease. N. Engl. J. Med. 368, 107–116. http://dx.doi.org/10.1056/
NEJMoa1211103.
Please cite this article in press as: Santos, L.E., et al. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav. Immun. (2015),
http://dx.doi.org/10.1016/j.bbi.2015.11.011
11
Jorge, R.E., Robinson, R.G., Moser, D., Tateno, A., Crespo-Facorro, B., Arndt, S., 2004.
Major depression following traumatic brain injury. Arch. Gen. Psychiatry 61,
42–50. http://dx.doi.org/10.1001/archpsyc.61.1.42.
Kales, H.C., Gitlin, L.N., Lyketsos, C.G., 2015. Assessment and management of
behavioral and psychological symptoms of dementia. BMJ 350, h369. http://dx.
doi.org/10.1136/bmj.h369.
Kang, J.Y., Lee, J.S., Kang, H., Lee, H.-W., Kim, Y.K., Jeon, H.J., Chung, J.-K., Lee, M.C.,
Cho, M.J., Lee, D.S., 2012. Regional cerebral blood flow abnormalities associated
with apathy and depression in Alzheimer disease. Alzheimer Dis. Assoc. Disord.
26, 217–224. http://dx.doi.org/10.1097/WAD.0b013e318231e5fc.
Karch, C.M., Cruchaga, C., Goate, A.M., 2014. Alzheimer’s disease genetics: from the
bench to the clinic. Neuron 83, 11–26. http://dx.doi.org/10.1016/j.
neuron.2014.05.041.
Karege, F., Perret, G., Bondolfi, G., Schwald, M., Bertschy, G., Aubry, J.M., 2002.
Decreased serum brain-derived neurotrophic factor levels in major depressed
patients. Psychiatry Res. 109, 143–148. http://dx.doi.org/10.1016/S0165-1781
(02)00005-7.
Kataoka, K., Hashimoto, H., Kawabe, J., Higashiyama, S., Akiyama, H., Shimada, A.,
Kai, T., Inoue, K., Shiomi, S., Kiriike, N., 2010. Frontal hypoperfusion in depressed
patients with dementia of Alzheimer type demonstrated on 3DSRT. Psychiatry
Clin. Neurosci. 64, 293–298. http://dx.doi.org/10.1111/j.1440-
1819.2010.02083.x.
Katon, W., Pedersen, H.S., Ribe, A.R., Fenger-Grøn, M., Davydow, D., Waldorff, F.B.,
Vestergaard, M., 2015. Effect of depression and diabetes mellitus on the risk for
dementia. JAMA Psychiatry 72, 612. http://dx.doi.org/
10.1001/jamapsychiatry.2015.0082.
Kempermann, G., 2002. Regulation of adult hippocampal neurogenesis –
implications for novel theories of major depression. Bipolar Disord. 4, 17–33.
http://dx.doi.org/10.1034/j.1399-5618.2002.40101.x.
Kempermann, G., Kronenberg, G., 2003. Depressed new neurons – adult
hippocampal neurogenesis and a cellular plasticity hypothesis of major
depression. Biol. Psychiatry 54, 499–503. http://dx.doi.org/10.1016/S0006-
3223(03)00319-6.
Kent, S., Bluthé, R.M., Kelley, K.W., Dantzer, R., 1992. Sickness behavior as a new
target for drug development. Trends Pharmacol. Sci. 13, 24–28. http://dx.doi.
org/10.1016/0165-6147(92)90012-U.
Khemka, V.K., Ganguly, A., Bagchi, D., Ghosh, A., Bir, A., Biswas, A., Chattopadhyay, S.,
Chakrabarti, S., 2014. Raised serum proinflammatory cytokines in Alzheimer’s
disease with depression. Aging Dis. 5, 170–176. http://dx.doi.org/10.14336/
AD.2014.0500170.
Kierdorf, K., Erny, D., Goldmann, T., Sander, V., Schulz, C., Perdiguero, E.G.,
Wieghofer, P., Heinrich, A., Riemke, P., Hölscher, C., Müller, D.N., Luckow, B.,
Brocker, T., Debowski, K., Fritz, G., Opdenakker, G., Diefenbach, A., Biber, K.,
Heikenwalder, M., Geissmann, F., Rosenbauer, F., Prinz, M., 2013. Microglia
emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent
pathways. Nat. Neurosci. 16, 273–280. http://dx.doi.org/10.1038/nn.3318.
Kim, H.J., Kim, W., Kong, S.Y., 2013. Antidepressants for neuro-regeneration: from
depression to Alzheimer’s disease. Arch. Pharm. Res. 36, 1279–1290. http://dx.
doi.org/10.1007/s12272-013-0238-8.
Klempin, F., Beis, D., Mosienko, V., Kempermann, G., Bader, M., Alenina, N., 2013.
Serotonin is required for exercise-induced adult hippocampal neurogenesis. J.
Neurosci. 33, 8270–8275. http://dx.doi.org/10.1523/JNEUROSCI.5855-12.2013.
Klunk, W.E., Engler, H., Nordberg, A., Wang, Y., Blomqvist, G., Holt, D.P., Bergström,
M., Savitcheva, I., Huang, G.F., Estrada, S., Ausén, B., Debnath, M.L., Barletta, J.,
Price, J.C., Sandell, J., Lopresti, B.J., Wall, A., Koivisto, P., Antoni, G., Mathis, C.A.,
Långström, B., 2004. Imaging Brain Amyloid in Alzheimer’s Disease with
Pittsburgh Compound-B. Ann. Neurol. 55, 306–319. http://dx.doi.org/10.1002/
ana.20009.
Knesevich, J.W., Martin, R.L., Berg, L., Danziger, W., 1983. Preliminary report on
affective symptoms in the early stages of senile dementia of the Alzheimer type.
Am. J. Psychiatry 140, 233–235.
Kobayashi, K., Imagama, S., Ohgomori, T., Hirano, K., Uchimura, K., Sakamoto, K.,
Hirakawa, A., Takeuchi, H., Suzumura, A., Ishiguro, N., Kadomatsu, K., 2013.
Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis. 4,
e525. http://dx.doi.org/10.1038/cddis.2013.54.
Köhler, O., Benros, M.E., Nordentoft, M., Farkouh, M.E., Iyengar, R.L., Mors, O., Krogh,
J., 2014. Effect of anti-inflammatory treatment on depression, depressive
symptoms, and adverse effects. JAMA Psychiatry 71, 1381. http://dx.doi.org/
10.1001/jamapsychiatry.2014.1611.
Kohman, R.A., DeYoung, E.K., Bhattacharya, T.K., Peterson, L.N., Rhodes, J.S., 2012.
Wheel running attenuates microglia proliferation and increases expression of a
proneurogenic phenotype in the hippocampus of aged mice. Brain Behav.
Immun. 26, 803–810. http://dx.doi.org/10.1016/j.bbi.2011.10.006.
Kohman, R.A., Bhattacharya, T.K., Wojcik, E., Rhodes, J.S., 2013. Exercise reduces
activation of microglia isolated from hippocampus and brain of aged mice. J.
Neuroinflamm. 10, 114. http://dx.doi.org/10.1186/1742-2094-10-114.
Kolodziejczak, M., Béchade, C., Gervasi, N., Irinopoulou, T., Banas, S.M., Cordier, C.,
Rebsam, A., Roumier, A., Maroteaux, L., 2015. Serotonin modulates
developmental microglia via 5-HT 2B receptors: potential implication during
synaptic refinement of retinogeniculate projections. ACS Chem. Neurosci. 6,
1219–1230. http://dx.doi.org/10.1021/cn5003489.
Kopczak, A., Stalla, G.K., Uhr, M., Lucae, S., Hennings, J., Ising, M., Holsboer, F.,
Kloiber, S., 2015. IGF-I in major depression and antidepressant treatment
response. Eur. Neuropsychopharmacol. 25, 864–872. http://dx.doi.org/10.1016/
j.euroneuro.2014.12.013.
12 L.E. Santos et al. / Brain, Behavior, and Immunity xxx (2015) xxx–xxx
Krabbe, G., Matyash, V., Pannasch, U., Mamer, L., Boddeke, H.W.G.M., Kettenmann,
H., 2012. Activation of serotonin receptors promotes microglial injury-induced
motility but attenuates phagocytic activity. Brain Behav. Immun. 26, 419–428.
http://dx.doi.org/10.1016/j.bbi.2011.12.002.
Kreisel, T., Frank, M.G., Licht, T., Reshef, R., Ben-Menachem-Zidon, O., Baratta, M.V.,
Maier, S.F., Yirmiya, R., 2014. Dynamic microglial alterations underlie stress-
induced depressive-like behavior and suppressed neurogenesis. Mol. Psychiatry
19, 699–709. http://dx.doi.org/10.1038/mp.2013.155.
Krstic, D., Knuesel, I., 2013. Deciphering the mechanism underlying late-onset
Alzheimer disease. Nat. Rev. Neurol. 9, 25–34. http://dx.doi.org/10.1038/
nrneurol.2012.236.
Lacasse, J.R., Leo, J., 2005. Serotonin and depression: a disconnect between the
advertisements and the scientific literature. PLoS Med. http://dx.doi.org/
10.1371/journal.pmed.0020392.
Lalancette-Hébert, M., Gowing, G., Simard, A., Weng, Y.C., Kriz, J., 2007. Selective
ablation of proliferating microglial cells exacerbates ischemic injury in the
brain. J. Neurosci. 27, 2596–2605. http://dx.doi.org/10.1523/JNEUROSCI.5360-
06.2007.
Lapchak, P.A., Araujo, D.M., Hefti, F., 1993. Systemic interleukin-1 beta decreases
brain-derived neurotrophic factor messenger RNA expression in the rat
hippocampal formation. Neuroscience 53, 297–301, 0306-4522(93)90196-M
[pii].
Laske, C., Stransky, E., Leyhe, T., Eschweiler, G.W., Maetzler, W., Wittorf, A.,
Soekadar, S., Richartz, E., Koehler, N., Bartels, M., Buchkremer, G., Schott, K.,
2007. BDNF serum and CSF concentrations in Alzheimer’s disease, normal
pressure hydrocephalus and healthy controls. J. Psychiatr. Res. 41, 387–394.
http://dx.doi.org/10.1016/j.jpsychires.2006.01.014.
Laws, S.M., Perneczky, R., Wagenpfeil, S., Müller, U., Förstl, H., Martins, R.N., Kurz, A.,
Riemenschneider, M., 2005. TNF polymorphisms in Alzheimer disease and
functional implications on CSF beta-amyloid levels. Hum. Mutat. 26, 29–35.
http://dx.doi.org/10.1002/humu.20180.
Lazarov, O., Marr, R.A., 2013. Of mice and men: neurogenesis, cognition, and
Alzheimer’s disease. Front. Aging Neurosci. 5, 1–8. http://dx.doi.org/10.3389/
fnagi.2013.00043.
Ledo, J.H., Azevedo, E.P., Clarke, J.R., Ribeiro, F.C., Figueiredo, C.P., Foguel, D., De
Felice, F.G., Ferreira, S.T., 2013. Amyloid-b oligomers link depressive-like
behavior and cognitive deficits in mice. Mol. Psychiatry 18, 1053–1054.
http://dx.doi.org/10.1038/mp.2012.168.
Lee, H.B., Lyketsos, C.G., 2003. Depression in Alzheimer’s disease: heterogeneity and
related issues. Biol. Psychiatry 54, 353–362. http://dx.doi.org/10.1016/S0006-
3223(03)00543-2.
Lee, Y.-K., Hou, S.-W., Lee, C.-C., Hsu, C.-Y., Huang, Y.-S., Su, Y.-C., 2013. Increased
Risk of Dementia in Patients with Mild Traumatic Brain Injury: A Nationwide
Cohort Study. PLoS One 8, e62422. http://dx.doi.org/10.1371/journal.
pone.0062422.
Levy-Cooperman, N., Burhan, A.M., Rafi-Tari, S., Kusano, M., Ramirez, J., Caldwell, C.,
Black, S.E., 2008. Frontal lobe hypoperfusion and depressive symptoms in
Alzheimer disease. J. Psychiatry Neurosci. 33, 218–226.
Li, Y., Du, X.F., Liu, C.S., Wen, Z.L., Du, J.L., 2012. Reciprocal regulation between
resting microglial dynamics and neuronal activity in vivo. Dev. Cell 23, 1189–
1202. http://dx.doi.org/10.1016/j.devcel.2012.10.027.
Lin, F., Suhr, J., Diebold, S., Heffner, K.L., 2014. Associations between depressive
symptoms and memory deficits vary as a function of insulin-like growth factor
(IGF-1) levels in healthy older adults. Psychoneuroendocrinology 42, 118–123.
http://dx.doi.org/10.1016/j.psyneuen.2014.01.006.
Lu, B., Nagappan, G., Guan, X., Nathan, P.J., Wren, P., 2013. BDNF-based synaptic
repair as a disease-modifying strategy for neurodegenerative diseases. Nat. Rev.
Neurosci. 14, 401–416, nrn3505 [pii]nr10.1038/nrn3505.
Luo, X.-G., Ding, J.-Q., Chen, S.-D., 2010. Microglia in the aging brain: relevance to
neurodegeneration. Mol. Neurodegener. 5, 12. http://dx.doi.org/10.1186/1750-
1326-5-12.
Lyketsos, C.G., Olin, J., 2002. Depression in Alzheimer’s disease: overview and
treatment. Biol. Psychiatry 52, 243–252. http://dx.doi.org/10.1016/S0006-3223
(02)01348-3.
Lyketsos, C.G., Steinberg, M., Tschanz, J.T., Norton, M.C., Steffens, D.C., Breitner, J.C.S.,
2000. Mental and behavioral disturbance in dementia: findings from the Cache
County Study on Memory in Aging. Am. J. Psychiatry 157, 708–714. http://dx.
doi.org/10.1176/appi.ajp.157.5.708.
Lyketsos, C.G., Lopez, O., Jones, B., Fitzpatrick, A.L., Breitner, J., DeKosky, S., 2002.
Prevalence of neuropsychiatric symptoms in dementia and mild cognitive
impairment: results from the cardiovascular health study. JAMA 288, 1475–
1483. http://dx.doi.org/10.1001/jama.288.12.1475.
Lyketsos, C.G., DelCampo, L., Steinberg, M., Miles, Q., Steele, C.D., Munro, C., Baker, A.
S., Sheppard, J.-M.E., Frangakis, C., Brandt, J., Rabins, P.V., 2003. Treating
depression in Alzheimer disease. Arch. Gen. Psychiatry 60, 737. http://dx.doi.
org/10.1001/archpsyc.60.7.737.
Lyketsos, C.G., Carrillo, M.C., Ryan, J.M., Khachaturian, A.S., Trzepacz, P., Amatniek, J.,
Cedarbaum, J., Brashear, R., Miller, D.S., 2011. Neuropsychiatric symptoms in
Alzheimer’s disease. Alzheimer’s Dement. http://dx.doi.org/10.1016/
j.jalz.2011.05.2410.
Lynch, M.A., 2014. The impact of neuroimmune changes on development of amyloid
pathology; relevance to Alzheimer’s disease. Immunology 141, 292–301. http://
dx.doi.org/10.1111/imm.12156.
Macchi, F., Homberg, J.R., Calabrese, F., Zecchillo, C., Racagni, G., Riva, M.A., Molteni,
R., 2013. Altered inflammatory responsiveness in serotonin transporter mutant
rats. J. Neuroinflamm. 10, 116. http://dx.doi.org/10.1186/1742-2094-10-116.
Please cite this article in press as: Santos, L.E., et al. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav. Immun. (2015),
http://dx.doi.org/10.1016/j.bbi.2015.11.011
Maddison, D.C., Giorgini, F., 2015. The kynurenine pathway and neurodegenerative
disease. Semin. Cell Dev. Biol. 44. http://dx.doi.org/10.1016/j.
semcdb.2015.03.002.
Maes, M., Leonard, B.E., Myint, A.M., Kubera, M., Verkerk, R., 2011. The new ‘‘5-HT”
hypothesis of depression. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 35,
702–721. http://dx.doi.org/10.1016/j.pnpbp.2010.12.017.
Malberg, J.E., Platt, B., Rizzo, S.J.S., Ring, R.H., Lucki, I., Schechter, L.E., Rosenzweig-
Lipson, S., 2007. Increasing the levels of insulin-like growth factor-I by an IGF
binding protein inhibitor produces anxiolytic and antidepressant-like effects.
Neuropsychopharmacology 32, 2360–2368. http://dx.doi.org/10.1038/sj.
npp.1301358.
Mapstone, M., Cheema, A.K., Fiandaca, M.S., Zhong, X., Mhyre, T.R., MacArthur, L.H.,
Hall, W.J., Fisher, S.G., Peterson, D.R., Haley, J.M., Nazar, M.D., Rich, S.A., Berlau,
D.J., Peltz, C.B., Tan, M.T., Kawas, C.H., Federoff, H.J., 2014. Plasma phospholipids
identify antecedent memory impairment in older adults. Nat. Med. 20, 415–
418. http://dx.doi.org/10.1038/nm.3466.
Mårtensson, U., Nässberger, L., 1993. Influence of antidepressants on mitogen
stimulation of human lymphocytes. Toxicol. In Vitro 7, 241–245. http://dx.doi.
org/10.1016/0887-2333(93)90007-R.
Martínez, A., Alcántara, S., Borrell, V., Del Río, J.A., Blasi, J., Otal, R., Campos, N.,
Boronat, A., Barbacid, M., Silos-Santiago, I., Soriano, E., 1998. TrkB and TrkC
signaling are required for maturation and synaptogenesis of hippocampal
connections. J. Neurosci. 18, 7336–7350.
Mattson, M.P., Maudsley, S., Martin, B., 2004. A neural signaling triumvirate that
influences ageing and age-related disease: insulin/IGF-1, BDNF and serotonin.
Ageing Res. Rev. 3, 445–464. http://dx.doi.org/10.1016/j.arr.2004.08.001.
Mawuenyega, K.G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J.C.,
Yarasheski, K.E., Bateman, R.J., 2010. Decreased clearance of CNS beta-amyloid
in Alzheimer’s disease. Science 330, 1774. http://dx.doi.org/
10.1126/science.1197623.
Merriam, A.E., Aronson, M.K., Gaston, P., Wey, S.L., Katz, I., 1988. The psychiatric
symptoms of Alzheimer’s disease. J. Am. Geriatr. Soc. 36, 7–12.
Michaud, M., Balardy, L., Moulis, G., Gaudin, C., Peyrot, C., Vellas, B., Cesari, M.,
Nourhashemi, F., 2013. Proinflammatory cytokines, aging, and age-related
diseases. J. Am. Med. Dir. Assoc. 14, 877–882. http://dx.doi.org/10.1016/
j.jamda.2013.05.009.
Mitschelen, M., Yan, H., Farley, J.A., Warrington, J.P., Han, S., Hereñú, C.B., Csiszar, A.,
Ungvari, Z., Bailey-Downs, L.C., Bass, C.E., Sonntag, W.E., 2011. Long-term
deficiency of circulating and hippocampal insulin-like growth factor I induces
depressive behavior in adult mice: a potential model of geriatric depression.
Neuroscience 185, 50–60. http://dx.doi.org/10.1016/j.
neuroscience.2011.04.032.
Mittelbronn, M., 2014. The M1/M2 immune polarization concept in microglia: a fair
transfer? Neuroimmunol. Neuroinflamm. 1, 6. http://dx.doi.org/10.4103/2347-
8659.135567.
Modrego, P.J., Ferrández, J., 2004. Depression in patients with mild cognitive
impairment increases the risk of developing dementia of Alzheimer type: a
prospective cohort study. Arch. Neurol. 61, 1290–1293. http://dx.doi.org/
10.1001/archneur.61.8.1290.
Molendijk, M.L., Spinhoven, P., Polak, M., Bus, B.A.A., Penninx, B.W.J.H., Elzinga, B.M.,
2014. Serum BDNF concentrations as peripheral manifestations of depression:
evidence from a systematic review and meta-analyses on 179 associations
(N=9484). Mol. Psychiatry 19, 791–800. http://dx.doi.org/10.1038/
mp.2013.105.
Moloney, A.M., Griffin, R.J., Timmons, S., O’Connor, R., Ravid, R., O’Neill, C., 2010.
Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease
indicate possible resistance to IGF-1 and insulin signalling. Neurobiol. Aging 31,
224–243. http://dx.doi.org/10.1016/j.neurobiolaging.2008.04.002.
Mondelli, V., Cattaneo, A., Murri, M.B., Forti, M., Di Handley, R., Hepgul, N., Miorelli,
A., Navari, S., Papadopoulos, A.S., Aitchison, K.J., Morgan, C., Murray, R.M.,
Dazzan, P., Pariante, C.M., 2011. Stress and inflammation reduce brain-derived
neurotrophic factor expression in first-episode psychosis: a pathway to smaller
hippocampal volume. J. Clin. Psychiatry 72, 1677–1684. http://dx.doi.org/
10.4088/JCP.10m06745.
Monje, M.L., Toda, H., Palmer, T.D., 2003. Inflammatory blockade restores adult
hippocampal neurogenesis. Science 302, 1760–1765. http://dx.doi.org/
10.1126/science.1088417.
Morales, I., Guzmán-Martínez, L., Cerda-Troncoso, C., Farías, G.A., Maccioni, R.B.,
2014. Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational
framework for the search of novel therapeutic approaches. Front. Cell. Neurosci.
8, 112. http://dx.doi.org/10.3389/fncel.2014.00112.
Morgan, S.C., Taylor, D.L., Pocock, J.M., 2004. Microglia release activators of
neuronal proliferation mediated by activation of mitogen-activated protein
kinase, phosphatidylinositol-3-kinase/Akt and delta-Notch signalling cascades.
J. Neurochem. 90, 89–101. http://dx.doi.org/10.1111/j.1471-4159.2004.
02461.x.
Mu, Y., Gage, F.H., 2011. Adult hippocampal neurogenesis and its role in Alzheimer’s
disease. Mol. Neurodegener. 6, 85. http://dx.doi.org/10.1186/1750-1326-6-85.
Müller, N., 2010. COX-2 inhibitors as antidepressants and antipsychotics: clinical
evidence. Curr. Opin. Investig. Drugs 11, 31–42.
Müller, N., Schwarz, M.J., 2007. The immune-mediated alteration of serotonin and
glutamate: towards an integrated view of depression. Mol. Psychiatry 12, 988–
1000. http://dx.doi.org/10.1038/sj.mp.4002006.
Myint, A.M., Kim, Y.K., 2003. Cytokine-serotonin interaction through IDO: a
neurodegeneration hypothesis of depression. Med. Hypotheses 61, 519–525.
http://dx.doi.org/10.1016/S0306-9877(03)00207-X.
 L.E. Santos et al. / Brain, Behavior, and Immunity xxx (2015) xxx–xxx
Nakanishi, M., Niidome, T., Matsuda, S., Akaike, A., Kihara, T., Sugimoto, H., 2007.
Microglia-derived interleukin-6 and leukaemia inhibitory factor promote
astrocytic differentiation of neural stem/progenitor cells. Eur. J. Neurosci. 25,
649–658. http://dx.doi.org/10.1111/j.1460-9568.2007.05309.x.
Naranjo, D.M., Fisher, L., Arean, P.A., Hessler, D., Mullan, J., 2011. Patients with type
2 diabetes at risk for major depressive disorder over time. Ann. Fam. Med. 9,
115–120. http://dx.doi.org/10.1370/afm.1212.
Nelson, J.C., 2001. Diagnosing and treating depression in the elderly. J. Clin.
Psychiatry 62, 18–22.
Nelson, J.C., Devanand, D.P., 2011. A systematic review and meta-analysis of
placebo-controlled antidepressant studies in people with depression and
dementia. J. Am. Geriatr. Soc. 59, 577–585. http://dx.doi.org/10.1111/j.1532-
5415.2011.03355.x.
Ng, F., Berk, M., Dean, O., Bush, A.I., 2008. Oxidative stress in psychiatric disorders:
evidence base and therapeutic implications. Int. J. Neuropsychopharmacol. 11,
851–876. http://dx.doi.org/10.1017/S1461145707008401.
Nimmerjahn, A., Kirchhoff, F., Helmchen, F., 2005. Resting microglial cells are highly
dynamic surveillants of brain parenchyma in vivo. Neuroforum 11, 95–96.
http://dx.doi.org/10.1126/science.1110647.
Norden, D.M., Muccigrosso, M.M., Godbout, J.P., 2015. Microglial priming and
enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and
neurodegenerative disease. Neuropharmacology 96, 29–41. http://dx.doi.org/
10.1016/j.neuropharm.2014.10.028.
O’Connor, J.C., Lawson, M.A., André, C., Moreau, M., Lestage, J., Castanon, N., Kelley,
K.W., Dantzer, R., 2009. Lipopolysaccharide-induced depressive-like behavior is
mediated by indoleamine 2,3-dioxygenase activation in mice. Mol. Psychiatry
14, 511–522. http://dx.doi.org/10.1038/sj.mp.4002148.
Okereke, O.I., Kang, J.H., Ma, J., Gaziano, J.M., Grodstein, F., 2006. Midlife plasma
insulin-like growth factor I and cognitive function in older men. J. Clin.
Endocrinol. Metab. 91, 4306–4312. http://dx.doi.org/10.1210/jc.2006-1325.
Olin, J.T., Schneider, L.S., Katz, I.R., Meyers, B.S., Alexopoulos, G.S., Breitner, J.C.,
Bruce, M.L., Caine, E.D., Cummings, J.L., Devanand, D.P., Krishnan, K.R.R.,
Lyketsos, C.G., Lyness, J.M., Rabins, P.V., Reynolds, C.F., Rovner, B.W., Steffens,
D.C., Tariot, P.N., Lebowitz, B.D., 2002. Provisional diagnostic criteria for
depression of Alzheimer disease. Am. J. Geriatr. Psychiatry 10, 125–128.
http://dx.doi.org/10.1097/00019442-200203000-00003.
Orre, M., Kamphuis, W., Osborn, L.M., Jansen, A.H.P., Kooijman, L., Bossers, K., Hol, E.
M., 2014. Isolation of glia from Alzheimer’s mice reveals inflammation and
dysfunction. Neurobiol. Aging 35, 2746–2760. http://dx.doi.org/10.1016/j.
neurobiolaging.2014.06.004.
Oshima, E., Terada, S., Sato, S., Ikeda, C., Oda, K., Inoue, S., Kawada, K., Yokota, O.,
Uchitomi, Y., 2014. Left frontal lobe hypoperfusion and depressive symptoms in
Alzheimer’s disease patients taking cholinesterase inhibitors. Psychiatry Res.
Neuroimaging 224, 319–323. http://dx.doi.org/10.1016/j.
pscychresns.2014.10.008.
Ott, A., Stolk, R.P., Hofman, A., Van Harskamp, F., Grobbee, D.E., Breteler, M.M.B.,
1996. Association of diabetes mellitus and dementia: the Rotterdam Study.
Diabetologia 39, 1392–1397. http://dx.doi.org/10.1007/s001250050588.
Ott, A., Stolk, R.P., van Harskamp, F., Pols, H.A., Hofman, A., Breteler, M.M., 1999.
Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology 53,
1937–1942. http://dx.doi.org/10.1016/S0140-6736(97)07541-7.
Ownby, R.L., Crocco, E., Acevedo, A., John, V., Loewenstein, D., 2006. Depression and
risk for Alzheimer disease. Arch. Gen. Psychiatry 63, 530–538.
Palmqvist, S., Sarwari, A., Wattmo, C., Bronge, L., Zhang, Y., Wahlund, L.O., Nägga, K.,
2011. Association between subcortical lesions and behavioral and psychological
symptoms in patients with Alzheimer’s disease. Dement. Geriatr. Cogn. Disord.
32, 417–423. http://dx.doi.org/10.1159/000335778.
Panza, F., Frisardi, V., Capurso, C., D’Introno, A., Colacicco, A.M., Imbimbo, B.P.,
Santamato, A., Vendemiale, G., Seripa, D., Pilotto, A., Capurso, A., Solfrizzi, V.,
2010. Late-life depression, mild cognitive impairment, and dementia: possible
continuum? Am. J. Geriatr. Psychiatry 18, 98–116. http://dx.doi.org/10.1097/
JGP.0b013e3181b0fa13.
Paolicelli, R.C., Gross, C.T., 2011. Microglia in development: linking brain wiring to
brain environment. Neuron Glia Biol. 7, 77–83. http://dx.doi.org/10.1017/
S1740925X12000105.
Paolicelli, R.C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., Giustetto,
M., Ferreira, T.A., Guiducci, E., Dumas, L., Ragozzino, D., Gross, C.T., 2011.
Synaptic pruning by microglia is necessary for normal brain development.
Science 333, 1456–1458. http://dx.doi.org/10.1126/science.1202529.
Pariante, C.M., Lightman, S.L., 2008. The HPA axis in major depression: classical
theories and new developments. Trends Neurosci. 31, 464–468. http://dx.doi.
org/10.1016/j.tins.2008.06.006.
Park, S.-E., Dantzer, R., Kelley, K.W., McCusker, R.H., 2011. Central administration of
insulin-like growth factor-I decreases depressive-like behavior and brain
cytokine expression in mice. J. Neuroinflamm. 8, 12. http://dx.doi.org/
10.1186/1742-2094-8-12.
Parkhurst, C.N., Yang, G., Ninan, I., Savas, J.N., Yates, J.R., Lafaille, J.J., Hempstead, B.L.,
Littman, D.R., Gan, W.B., 2013. Microglia promote learning-dependent synapse
formation through brain-derived neurotrophic factor. Cell 155, 1596–1609.
http://dx.doi.org/10.1016/j.cell.2013.11.030.
Parpura, V., Zorec, R., 2010. Gliotransmission: exocytotic release from astrocytes.
Brain Res. Rev. 63, 83–92. http://dx.doi.org/10.1016/j.brainresrev.2009.11.008.
Pascoe, M.C., Crewther, S.G., Carey, L.M., Crewther, D.P., 2011. Inflammation and
depression: why poststroke depression may be the norm and not the exception.
Int. J. Stroke 6, 128–135. http://dx.doi.org/10.1111/j.1747-4949.2010.00565.x.
Please cite this article in press as: Santos, L.E., et al. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav. Immun. (2015),
http://dx.doi.org/10.1016/j.bbi.2015.11.011
13
Paslakis, G., Blum, W.F., Deuschle, M., 2012. Intranasal insulin-like growth factor I
(IGF-I) as a plausible future treatment of depression. Med. Hypotheses 79, 222–
225. http://dx.doi.org/10.1016/j.mehy.2012.04.045.
Peng, S., Wuu, J., Mufson, E.J., Fahnestock, M., 2005. Precursor form of brain-derived
neurotrophic factor and mature brain-derived neurotrophic factor are
decreased in the pre-clinical stages of Alzheimer’s disease. J. Neurochem. 93,
1412–1421. http://dx.doi.org/10.1111/j.1471-4159.2005.03135.x.
Perry, V.H., Holmes, C., 2014. Microglial priming in neurodegenerative disease. Nat.
Rev. Neurol. 10, 217–224. http://dx.doi.org/10.1038/nrneurol.2014.38.
Perry, V.H., Cunningham, C., Holmes, C., 2007. Systemic infections and inflammation
affect chronic neurodegeneration. Nat. Rev. Immunol. 7, 161–167. http://dx.doi.
org/10.1038/nri2015.
Pocock, J.M., Kettenmann, H., 2007. Neurotransmitter receptors on microglia.
Trends Neurosci. 30, 527–535. http://dx.doi.org/10.1016/j.tins.2007.07.007.
Porta-Etessam, J., Tobaruela-González, J.L., Rabes-Berendes, C., 2011. Depression in
patients with moderate Alzheimer disease. Alzheimer Dis. Assoc. Disord. 25,
317–325. http://dx.doi.org/10.1097/WAD.0b013e31820e7c45.
Powell, T.R., Schalkwyk, L.C., Heffernan, A.L., Breen, G., Lawrence, T., Price, T.,
Farmer, A.E., Aitchison, K.J., Craig, I.W., Danese, A., Lewis, C., McGuffin, P., Uher,
R., Tansey, K.E., D’Souza, U.M., 2013. Tumor necrosis factor and its targets in the
inflammatory cytokine pathway are identified as putative transcriptomic
biomarkers for escitalopram response. Eur. Neuropsychopharmacol. 23, 1105–
1114. http://dx.doi.org/10.1016/j.euroneuro.2012.09.009.
Prinz, M., Priller, J., 2014. Microglia and brain macrophages in the molecular age:
from origin to neuropsychiatric disease. Nat. Rev. Neurosci. 15, 300–312. http://
dx.doi.org/10.1038/nrn3722.
Raison, C.L., Capuron, L., Miller, A.H., 2006. Cytokines sing the blues: inflammation
and the pathogenesis of depression. Trends Immunol. 27, 24–31. http://dx.doi.
org/10.1016/j.it.2005.11.006.
Rauskolb, S., Zagrebelsky, M., Dreznjak, A., Deogracias, R., Matsumoto, T., Wiese, S.,
Erne, B., Sendtner, M., Schaeren-Wiemers, N., Korte, M., Barde, Y.-A., 2010.
Global deprivation of brain-derived neurotrophic factor in the CNS reveals an
area-specific requirement for dendritic growth. J. Neurosci. 30, 1739–1749.
http://dx.doi.org/10.1523/JNEUROSCI.5100-09.2010.
Reichenberg, A., Yirmiya, R., Schuld, A., Kraus, T., Haack, M., Morag, A., Pollmächer,
T., 2001. Cytokine-associated emotional and cognitive disturbances in humans.
Arch. Gen. Psychiatry 58, 445–452. http://dx.doi.org/10.1001/
archpsyc.58.5.445.
Renault, P.F., 1987. Psychiatric complications of long-term interferon alfa therapy.
Arch. Intern. Med. 147, 1577. http://dx.doi.org/10.1001/
archinte.1987.00370090055011.
Ribeiro Xavier, A.L., Kress, B.T., Goldman, S.A., Lacerda de Menezes, J.R., Nedergaard,
M., 2015. A distinct population of microglia supports adult neurogenesis in the
subventricular zone. J. Neurosci. 35, 11848–11861. http://dx.doi.org/10.1523/
JNEUROSCI.1217-15.2015.
Richard, E., Reitz, C., Honig, L.H., Schupf, N., Tang, M.X., Manly, J.J., Mayeux, R.,
Devanand, D., Luchsinger, J.A., 2013. Late-life depression, mild cognitive
impairment, and dementia. JAMA Neurol. 70, 383. http://dx.doi.org/
10.1001/jamaneurol.2013.603.
Rivest, S., 2015. TREM2 enables amyloid b clearance by microglia. Cell Res. 25, 535–
536. http://dx.doi.org/10.1038/cr.2015.37.
Roberts, R., Knopman, D.S., 2013. Classification and epidemiology of MCI. Clin.
Geriatr. Med. 29, 753–772. http://dx.doi.org/10.1016/j.cger.2013.07.003.
Roberts, K.F., Elbert, D.L., Kasten, T.P., Patterson, B.W., Sigurdson, W.C., Connors, R.E.,
Ovod, V., Munsell, L.Y., Mawuenyega, K.G., Miller-Thomas, M.M., Moran, C.J.,
Cross, D.T., Derdeyn, C.P., Bateman, R.J., 2014. Amyloid-b efflux from the central
nervous system into the plasma. Ann. Neurol. 76, 837–844. http://dx.doi.org/
10.1002/ana.24270.
Rodríguez, J.J., Noristani, H.N., Verkhratsky, A., 2012. The serotonergic system in
ageing and Alzheimer’s disease. Prog. Neurobiol. 99, 15–41. http://dx.doi.org/
10.1016/j.pneurobio.2012.06.010.
Roumestan, C., Michel, A., Bichon, F., Portet, K., Detoc, M., Henriquet, C., Jaffuel, D.,
Mathieu, M., 2007. Anti-inflammatory properties of desipramine and fluoxetine.
Respir. Res. 8, 35. http://dx.doi.org/10.1186/1465-9921-8-35.
Ruhé, H.G., Mason, N.S., Schene, A.H., 2007. Mood is indirectly related to serotonin,
norepinephrine and dopamine levels in humans: a meta-analysis of
monoamine depletion studies. Mol. Psychiatry 12, 331–359. http://dx.doi.org/
10.1038/sj.mp.4001949.
Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Nierenberg, A.A., Stewart, J.W., Warden, D.,
Niederehe, G., Thase, M.E., Lavori, P.W., Lebowitz, B.D., McGrath, P.J.,
Rosenbaum, J.F., Sackeim, H.A., Kupfer, D.J., Luther, J., Fava, M., 2006. Acute
and longer-term outcomes in depressed outpatients requiring one or several
treatment steps: a STAR*D report. Am. J. Psychiatry 163, 1905–1917. http://dx.
doi.org/10.1176/appi.ajp.163.11.1905.
Sabri, O., Seibyl, J., Rowe, C., Barthel, H., 2015. Beta-amyloid imaging with
florbetaben. Clin. Transl. Imaging 3, 13–26. http://dx.doi.org/10.1007/s40336-
015-0102-6.
Sacre, S., Medghalchi, M., Gregory, B., Brennan, F., Williams, R., 2010. Fluoxetine and
citalopram exhibit potent antiinflammatory activity in human and murine
models of rheumatoid arthritis and inhibit toll-like receptors. Arthritis Rheum.
62, 683–693. http://dx.doi.org/10.1002/art.27304.
Sadovnick, A.D., Remick, R.A., Allen, J., Swartz, E., Yee, I.M., Eisen, K., Farquhar, R.,
Hashimoto, S.A., Hooge, J., Kastrukoff, L.F., Morrison, W., Nelson, J., Oger, J., Paty,
D.W., 1997. Depression and multiple sclerosis. Eur. Psychiatry J. Assoc. Eur.
Psychiatry 46, 628–632. http://dx.doi.org/10.1212/WNL.46.3.628.
14 L.E. Santos et al. / Brain, Behavior, and Immunity xxx (2015) xxx–xxx
Saunders, A.M., Strittmatter, W.J., Schmechel, D., George-Hyslop, P.H., Pericak-
Vance, M.A., Joo, S.H., Rosi, B.L., Gusella, J.F., Crapper-MacLachlan, D.R., Alberts,
M.J., 1993. Association of apolipoprotein E allele epsilon 4 with late-onset
familial and sporadic Alzheimer’s disease. Neurology 43, 1467–1472. http://dx.
doi.org/10.1212/WNL.43.8.1467.
Schildkraut, J.J., 1965. The catecholamine hypothesis of affective disorders: a review
of supporting evidence. Am. J. Psychiatry 122, 509–522. http://dx.doi.org/
10.1176/appi.ajp.122.5.509.
Sciacca, F., Ferri, C., Licastro, F., Veglia, F., Biunno, I., Gavazzi, A., Calabrese, E.,
Martinelli Boneschi, F., Sorbi, S., Mariani, C., Franceschi, M., Grimaldi, L.M., 2003.
Interleukin-1B polymorphism is associated with age at onset of Alzheimer’s
disease. Neurobiol. Aging 24, 927–931. http://dx.doi.org/10.1016/S0197-4580
(03)00011-3.
Sepehry, A.A., Lee, P.E., Hsiung, G.Y.R., Beattie, B.L., Jacova, C., 2012. Effect of
selective serotonin reuptake inhibitors in Alzheimer’s disease with comorbid
depression: a meta-analysis of depression and cognitive outcomes. Drugs Aging
29, 793–806. http://dx.doi.org/10.1007/s40266-012-0012-5.
Setiawan, E., Wilson, A.A., Mizrahi, R., Rusjan, P.M., Miler, L., Rajkowska, G., Suridjan,
I., Kennedy, J.L., Rekkas, P.V., Houle, S., Meyer, J.H., 2015. Role of translocator
protein density, a marker of neuroinflammation, in the brain during major
depressive episodes. JAMA Psychiatry 72, 268. http://dx.doi.org/
10.1001/jamapsychiatry.2014.2427.
Sheline, Y.I., West, T., Yarasheski, K., Swarm, R., Jasielec, M.S., Fisher, J.R., Ficker, W.
D., Yan, P., Xiong, C., Frederiksen, C., Grzelak, M.V., Chott, R., Bateman, R.J.,
Morris, J.C., Mintun, M.A., Lee, J.-M., Cirrito, J.R., 2014. An antidepressant
decreases CSF Ab production in healthy individuals and in transgenic AD mice.
Sci. Transl. Med. 6, 236re4. http://dx.doi.org/10.1126/scitranslmed.3008169.
Smith, R.S., 1991. The macrophage theory of depression. Med. Hypotheses 35, 298–
306. http://dx.doi.org/10.1016/0306-9877(91)90272-Z.
Soczynska, J.K., Mansur, R.B., Brietzke, E., Swardfager, W., Kennedy, S.H.,
Woldeyohannes, H.O., Powell, A.M., Manierka, M.S., McIntyre, R.S., 2012.
Novel therapeutic targets in depression: minocycline as a candidate
treatment. Behav. Brain Res. http://dx.doi.org/10.1016/j.bbr.2012.07.026.
Son, J.H., Han, D.H., Min, K.J., Kee, B.S., 2013. Correlation between gray matter
volume in the temporal lobe and depressive symptoms in patients with
Alzheimer’s disease. Neurosci. Lett. 548, 15–20. http://dx.doi.org/10.1016/j.
neulet.2013.05.021.
Sonntag, W.E., Deak, F., Ashpole, N., Toth, P., Csiszar, A., Freeman, W., Ungvari, Z.,
2013. Insulin-like growth factor-1 in CNS and cerebrovascular aging. Front.
Aging Neurosci. 5, 27. http://dx.doi.org/10.3389/fnagi.2013.00027.
Starkstein, S.E., Jorge, R., Mizrahi, R., Robinson, R.G., 2005. The construct of minor
and major depression in Alzheimer’s disease. Am. J. Psychiatry 162, 2086–2093.
http://dx.doi.org/10.1176/appi.ajp.162.11.2086.
Steinberg, M., Shao, H., Zandi, P., Lyketsos, C.G., Welsh-bohmer, K.A., Norton, M.C.,
Breitner, J.C.S., Steffens, D.C., Tschanz, J.T.Cache County Investigators, 2008.
Point and 5-year period prevalence of neuropsychiatric symptoms in dementia:
the Cache County Study. Int. J. Geriatr. Psychiatry 23, 170–177. http://dx.doi.
org/10.1002/gps.
Steiner, J., Walter, M., Gos, T., Guillemin, G.J., Bernstein, H.-G., Sarnyai, Z., Mawrin, C.,
Brisch, R., Bielau, H., Zu Schwabedissen, L., Bogerts, B., Myint, A.-M., 2011.
Severe depression is associated with increased microglial quinolinic acid in
subregions of the anterior cingulate gyrus: evidence for an immune-modulated
glutamatergic neurotransmission? J. Neuroinflamm. 8, 94. http://dx.doi.org/
10.1186/1742-2094-8-94.
Su, F., Yi, H., Xu, L., Zhang, Z., 2015. Fluoxetine and S-citalopram inhibit M1
activation and promote M2 activation of microglia in vitro. Neuroscience 294,
60–68. http://dx.doi.org/10.1016/j.neuroscience.2015.02.028.
Sun, L.Y., 2006. Hippocampal IGF-1 expression, neurogenesis and slowed aging:
clues to longevity from mutant mice. Age (Omaha) 28, 181–189. http://dx.doi.
org/10.1007/s11357-006-9009-5.
Swardfager, W., Lanctt, K., Rothenburg, L., Wong, A., Cappell, J., Herrmann, N., 2010.
A meta-analysis of cytokines in Alzheimer’s disease. Biol. Psychiatry 68, 930–
941. http://dx.doi.org/10.1016/j.biopsych.2010.06.012.
Szczêsny, E., OElusarczyk, J., Glombik, K., Budziszewska, B., Kubera, M., Lasoñz, W.,
Basta-Kaim, A., 2013. Possible contribution of IGF-1 to depressive disorder.
Pharmacol. Rep. 65, 1622–1631.
Takahashi, K., Rochford, C.D.P., Neumann, H., 2005. Clearance of apoptotic neurons
without inflammation by microglial triggering receptor expressed on myeloid
cells-2. J. Exp. Med. 201, 647–657. http://dx.doi.org/10.1084/jem.20041611.
Talbot, K., Wang, H.-Y., Kazi, H., Han, L.-Y., Bakshi, K.P., Stucky, A., Fuino, R.L.,
Kawaguchi, K.R., Samoyedny, A.J., Wilson, R.S., Arvanitakis, Z., Schneider, J.A.,
Wolf, B.A., Bennett, D.A., Trojanowski, J.Q., Arnold, S.E., 2012. Demonstrated
brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1
resistance, IRS-1 dysregulation, and cognitive decline. J. Clin. Invest. 122, 1316–
1338. http://dx.doi.org/10.1172/JCI59903.
Taraz, M., Khatami, M., Dashti-khavidaki, S., Akhonzadeh, S., 2013. Sertraline
decreases serum level of interleukin-6 (IL-6) in hemodialysis patients with
depression: results of a randomized double-blind, placebo-controlled clinical
trial. Int. Immunopharmacol. 17, 917–923. http://dx.doi.org/10.1016/j.
intimp.2013.09.020.
Teng, E., Ringman, J.M., Ross, L.K., Mulnard, R.A., Dick, M.B., Bartzokis, G., Davies, H.
D., Galasko, D., Hewett, L., Mungas, D., Reed, B.R., Schneider, L.S., Segal-Gidan, F.,
Yaffe, K., Cummings, J.L., 2008. Diagnosing depression in Alzheimer disease with
the national institute of mental health provisional criteria. Am. J. Geriatr.
Psychiatry 16, 469–477. http://dx.doi.org/10.1097/JGP.0b013e318165dbae.
Please cite this article in press as: Santos, L.E., et al. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav. Immun. (2015),
http://dx.doi.org/10.1016/j.bbi.2015.11.011
Terada, S., Oshima, E., Sato, S., Ikeda, C., Nagao, S., Hayashi, S., Hayashibara, C.,
Yokota, O., Uchitomi, Y., 2014. Depressive symptoms and regional cerebral
blood flow in Alzheimer’s disease. Psychiatry Res. 221, 86–91. http://dx.doi.org/
10.1016/j.pscychresns.2013.11.002.
Trivedi, M.H., Rush, A.J., Wisniewski, S.R., Nierenberg, A.A., Warden, D., Ritz, L.,
Norquist, G., Howland, R.H., Lebowitz, B., McGrath, P.J., Shores-Wilson, K., Biggs,
M.M., Balasubramani, G.K., Fava, M., 2006. Evaluation of outcomes with
citalopram for depression using measurement-based care in STAR*D:
implications for clinical practice. Am. J. Psychiatry 163, 28–40. http://dx.doi.
org/10.1176/appi.ajp.163.1.28.
Turnbull, I.R., Gilfillan, S., Cella, M., Aoshi, T., Miller, M., Piccio, L., Hernandez, M.,
Colonna, M., 2006. Cutting edge: TREM-2 attenuates macrophage activation. J.
Immunol. 177, 3520–3524. http://dx.doi.org/10.4049/jimmunol.177.6.3520.
Tynan, R.J., Weidenhofer, J., Hinwood, M., Cairns, M.J., Day, T.A., Walker, F.R., 2012. A
comparative examination of the anti-inflammatory effects of SSRI and SNRI
antidepressants on LPS stimulated microglia. Brain Behav. Immun. 26, 469–479.
http://dx.doi.org/10.1016/j.bbi.2011.12.011.
Ueno, M., Fujita, Y., Tanaka, T., Nakamura, Y., Kikuta, J., Ishii, M., Yamashita, T., 2013.
Layer V cortical neurons require microglial support for survival during postnatal
development. Nat. Neurosci. 16, 543–551. http://dx.doi.org/10.1038/nn.3358.
Ulrich, J.D., Finn, M.B., Wang, Y., Shen, A., Mahan, T.E., Jiang, H., Stewart, F.R., Piccio,
L., Colonna, M., Holtzman, D.M., 2014. Altered microglial response to Abeta
plaques in APPPS1-21 mice heterozygous for TREM2. Mol. Neurodegener. 9, 20.
http://dx.doi.org/10.1186/1750-1326-9-20.
Vécsei, L., Szalárdy, L., Fülöp, F., Toldi, J., 2013. Kynurenines in the CNS: recent
advances and new questions. Nat. Rev. Drug Discov. 12, 64–82. http://dx.doi.
org/10.1038/nrd3793.
Ventriglia, M., Zanardini, R., Bonomini, C., Zanetti, O., Volpe, D., Pasqualetti, P.,
Gennarelli, M., Bocchio-Chiavetto, L., 2013. Serum brain-derived neurotrophic
factor levels in different neurological diseases. Biomed Res. Int. 2013, 1–7.
http://dx.doi.org/10.1155/2013/901082.
Videbech, P., 2004. Hippocampal volume and depression: a meta-analysis of MRI
studies. Am. J. Psychiatry 161, 1957–1966. http://dx.doi.org/10.1176/appi.
ajp.161.11.1957.
Vilalta-Franch, J., Garre-Olmo, J., Lopez-Pousa, S., Turon-Estrada, A., Lozano-Gallego,
M., Hernandez-Ferrandiz, M., Pericot-Nierga, I., Feijoo-Lorza, R., 2006.
Comparison of different clinical diagnostic criteria for depression in
Alzheimer disease. Am. J. Geriatr. Psychiatry 14, 589–597, doi: 10.1097/01.
JGP.0000209396.15788.9d.
Viola, K.L., Sbarboro, J., Sureka, R., De, M., Bicca, M.A., Wang, J., Vasavada, S.,
Satpathy, S., Wu, S., Joshi, H., Velasco, P.T., MacRenaris, K., Waters, E.A., Lu, C.,
Phan, J., Lacor, P., Prasad, P., Dravid, V.P., Klein, W.L., 2014. Towards non-
invasive diagnostic imaging of early-stage Alzheimer’s disease. Nat.
Nanotechnol. 10, 91–98. http://dx.doi.org/10.1038/nnano.2014.254.
Von Bernhardi, R., Tichauer, J.E., Eugenín, J., 2010. Aging-dependent changes of
microglial cells and their relevance for neurodegenerative disorders. J.
Neurochem. 112, 1099–1114. http://dx.doi.org/10.1111/j.1471-
4159.2009.06537.x.
Vukovic, J., Colditz, M.J., Blackmore, D.G., Ruitenberg, M.J., Bartlett, P.F., 2012.
Microglia modulate hippocampal neural precursor activity in response to
exercise and aging. J. Neurosci. 32, 6435–6443. http://dx.doi.org/10.1523/
JNEUROSCI.5925-11.2012.
Walker, F.R., 2013. A critical review of the mechanism of action for the selective
serotonin reuptake inhibitors: do these drugs possess anti-inflammatory
properties and how relevant is this in the treatment of depression?
Neuropharmacology 67, 304–317. http://dx.doi.org/10.1016/j.
neuropharm.2012.10.002.
Walton, N.M., Sutter, B.M., Laywell, E.D., Levkoff, L.H., Kearns, S.M., Marshall, G.P.,
Scheffler, B., Steindler, D.A., 2006. Microglia instruct subventricular zone
neurogenesis. Glia 54, 815–825. http://dx.doi.org/10.1002/glia.20419.
Wang, T., 2015. TNF-alpha G308A polymorphism and the susceptibility to
Alzheimer’s Disease: an updated meta-analysis. Arch. Med. Res. 46 (24–30),
e1. http://dx.doi.org/10.1016/j.arcmed.2014.12.006.
Wang, Y., Cella, M., Mallinson, K., Ulrich, J.D., Young, K.L., Robinette, M.L., Gilfillan, S.,
Krishnan, G.M., Sudhakar, S., Zinselmeyer, B.H., Holtzman, D.M., Cirrito, J.R.,
Colonna, M., 2015. TREM2 lipid sensing sustains the microglial response in an
Alzheimer’s disease model. Cell 160, 1061–1071. http://dx.doi.org/10.1016/
j.cell.2015.01.049.
Watanabe, T., Miyazaki, A., Katagiri, T., Yamamoto, H., Idei, T., Iguchi, T., 2005.
Relationship between serum insulin-like growth factor-1 levels and Alzheimer’s
disease and vascular dementia. J. Am. Geriatr. Soc. 53, 1748–1753. http://dx.doi.
org/10.1111/j.1532-5415.2005.53524.x.
Westwood, A.J., Beiser, A., Decarli, C., Harris, T.B., Chen, T.C., He, X.-M., Roubenoff, R.,
Pikula, A., Au, R., Braverman, L.E., Wolf, P.A., Vasan, R.S., Seshadri, S., 2014.
Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy.
Neurology 82, 1613–1619. http://dx.doi.org/10.1212/WNL.0000000000000382.
Wichers, M.C., Maes, M., 2004. The role of indoleamine 2,3-dioxygenase (IDO) in the
pathophysiology of interferon-alpha-induced depression. J. Psychiatry Neurosci.
29, 11–17.
Wilcock, D.M., 2012. A changing perspective on the role of neuroinflammation in
Alzheimer’s disease. Int. J. Alzheimers. Dis. 2012, 1–7. http://dx.doi.org/
10.1155/2012/495243.
Wolkowitz, O.M., Wolf, J., Shelly, W., Rosser, R., Burke, H.M., Lerner, G.K., Reus, V.I.,
Nelson, J.C., Epel, E.S., Mellon, S.H., 2011. Serum BDNF levels before treatment
predict SSRI response in depression. Prog. Neuro-Psychopharmacol. Biol.
Psychiatry 35, 1623–1630. http://dx.doi.org/10.1016/j.pnpbp.2011.06.013.
 L.E. Santos et al. / Brain, Behavior, and Immunity xxx (2015) xxx–xxx
Yasutake, C., Kuroda, K., Yanagawa, T., Okamura, T., Yoneda, H., 2006. Serum BDNF,
TNF-alpha and IL-1beta levels in dementia patients: comparison between
Alzheimer’s disease and vascular dementia. Eur. Arch. Psychiatry Clin. Neurosci.
256, 402–406. http://dx.doi.org/10.1007/s00406-006-0652-8.
Ye, S.M., Johnson, R.W., 1999. Increased interleukin-6 expression by microglia from
brain of aged mice. J. Neuroimmunol. 93, 139–148. http://dx.doi.org/10.1016/
S0165-5728(98)00217-3.
Yesavage, J.A., Brink, T.L., Rose, T.L., Lum, O., Huang, V., Adey, M., Leirer, V.O., 1982.
Development and validation of a geriatric depression screening scale: a
preliminary report. J. Psychiatr. Res. 17, 37–49. http://dx.doi.org/10.1016/
0022-3956(82)90033-4.
Yirmiya, R., 1996. Endotoxin produces a depressive-like episode in rats. Brain Res.
711, 163–174. http://dx.doi.org/10.1016/0006-8993(95)01415-2.
Yirmiya, R., Rimmerman, N., Reshef, R., 2015. Depression as a microglial disease.
Trends Neurosci. 38, 637–658. http://dx.doi.org/10.1016/j.tins.2015.08.001.
Yu, H., Chen, Z., 2011. The role of BDNF in depression on the basis of its location in
the neural circuitry. Acta Pharmacol. Sin. 32, 3–11. http://dx.doi.org/10.1038/
aps.2010.184.
Yu, D., Tao, B.-B., Yang, Y.-Y., Du, L.-S., Yang, S.-S., He, X.-J., Zhu, Y.-W., Yan, J.-K.,
Yang, Q., 2015. The IDO inhibitor coptisine ameliorates cognitive impairment in
a mouse model of Alzheimer’s disease. J. Alzheimers. Dis. 43, 291–302. http://
dx.doi.org/10.3233/JAD-140414.
Yuan, H., Chen, R., Wu, L., Chen, Q., Hu, A., Zhang, T., Wang, Z., Zhu, X., 2015. The
regulatory mechanism of neurogenesis by IGF-1 in adult mice. Mol. Neurobiol.
51, 512–522. http://dx.doi.org/10.1007/s12035-014-8717-6.
Zhan, Y., Paolicelli, R.C., Sforazzini, F., Weinhard, L., Bolasco, G., Pagani, F., Vyssotski,
A.L., Bifone, A., Gozzi, A., Ragozzino, D., Gross, C.T., 2014. Deficient neuron-
microglia signaling results in impaired functional brain connectivity and social
behavior. Nat. Neurosci. 17, 400–406. http://dx.doi.org/10.1038/nn.3641.
Please cite this article in press as: Santos, L.E., et al. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav. Immun. (2015),
http://dx.doi.org/10.1016/j.bbi.2015.11.011
15
Zhang, F., Zhou, H., Wilson, B.C., Shi, J.-S., Hong, J.-S., Gao, H.-M., 2012. Fluoxetine
protects neurons against microglial activation-mediated neurotoxicity.
Parkinsonism Relat. Disord. 18, S213–S217. http://dx.doi.org/10.1016/S1353-
8020(11)70066-9.
Zheng, L.S., Hitoshi, S., Kaneko, N., Takao, K., Miyakawa, T., Tanaka, Y., Xia, H.,
Kalinke, U., Kudo, K., Kanba, S., Ikenaka, K., Sawamoto, K., 2014. Mechanisms for
interferon-a-induced depression and neural stem cell dysfunction. Stem Cell
Rep. 3, 73–84. http://dx.doi.org/10.1016/j.stemcr.2014.05.015.
Zheng, L.-S., Kaneko, N., Sawamoto, K., 2015. Minocycline treatment ameliorates
interferon-alpha-induced neurogenic defects and depression-like behaviors in
mice. Front. Cell. Neurosci. 9, 1–10. http://dx.doi.org/10.3389/fncel.2015.00005.
Ziebell, J.M., Morganti-Kossmann, M.C., 2010. Involvement of pro- and anti-
inflammatory cytokines and chemokines in the pathophysiology of traumatic
brain injury. Neurotherapeutics 7, 22–30. http://dx.doi.org/10.1016/j.
nurt.2009.10.016.
Ziv, Y., Schwartz, M., 2008. Immune-based regulation of adult neurogenesis:
implications for learning and memory. Brain Behav. Immun. 22, 167–176.
http://dx.doi.org/10.1016/j.bbi.2007.08.006.
Ziv, Y., Ron, N., Butovsky, O., Landa, G., Sudai, E., Greenberg, N., Cohen, H., Kipnis, J.,
Schwartz, M., 2006. Immune cells contribute to the maintenance of
neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 9,
268–275. http://dx.doi.org/10.1038/nn1629.
Zubenko, G.S., Zubenko, W.N., McPherson, S., Spoor, E., Marin, D.B., Farlow, M.R.,
Smith, G.E., Geda, Y.E., Cummings, J.L., Petersen, R.C., Sunderland, T., 2003. A
collaborative study of the emergence and clinical features of the major
depressive syndrome of Alzheimer’s disease. Am. J. Psychiatry 160, 857–866.
http://dx.doi.org/10.1176/appi.ajp.160.5.857.