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DOI 10.3233/JAD-2010-091249
IOS Press
Abstract. Epidemiologic studies have increasingly suggested that caffeine/coffee could be an effective therapeutic against
Alzheimer’s disease (AD). We have utilized a transgenic mouse model for AD in well-controlled studies to determine if caffeine
and/or coffee have beneficial actions to protect against or reverse AD-like cognitive impairment and AD pathology. AD mice
given caffeine in their drinking water from young adulthood into older age showed protection against memory impairment
and lower brain levels of the abnormal protein (amyloid-β; Aβ) thought to be central to AD pathogenesis. Moreover, “aged”
cognitively-impaired AD mice exhibited memory restoration and lower brain Aβ levels following only 1–2 months of caffeine
treatment. We believe that the cognitive benefits of chronic caffeine administration in AD mice are due to caffeine itself, and not
metabolites of caffeine; this, because our long-term administration of theophylline to AD mice provided no cognitive benefits. In
acute studies involving AD mice, one oral caffeine treatment quickly reduced both brain and plasma Aβ levels – similarly rapid
alterations in plasma Aβ levels were seen in humans following acute caffeine administration. “Caffeinated” coffee provided to
AD mice also quickly decreased plasma Aβ levels, but not “decaffeinated” coffee, suggesting that caffeine is critical to decreasing
blood Aβ levels. Caffeine appears to provide its disease-modifying effects through multiple mechanisms, including a direct
reduction of Aβ production through suppression of both β- and γ-secretase levels. These results indicate a surprising ability of
moderate caffeine intake (the human equivalent of 500 mg caffeine or 5 cups of coffee per day) to protect against or treat AD in
a mouse model for the disease and a therapeutic potential for caffeine against AD in humans.
ISSN 1387-2877/10/$27.50 2010 – IOS Press and the authors. All rights reserved
S118 G.W. Arendash and C. Cao / Caffeine and Coffee as Therapeutics Against AD
Fig. 1. Protective/treatment effects of caffeine intake on Aβ production/aggregation and memory in AD transgenic (Tg) mice when caffeine
consumption is started during young adulthood (life-long caffeine) or after development of AD pathology/memory impairment.
Tg mice [11]. Exactly how caffeine suppresses both of protection-based study, results in mice receiving a dai-
these secretases was explored in our follow-up studies ly caffeine intake of approximately 1.5 mg/day (e.g.,
(see next section). Our initial study [11] provided the the human equivalent of 500 mg caffeine or 5 cups of
first evidence that caffeine can directly affect AD patho- coffee per day). Prior to caffeine treatment, aged Tg
genesis by suppressing levels of both enzymes need- mice were substantially impaired in a working mem-
ed for Aβ production. Moreover, we have shown that ory task, the radial arm water maze. Following caf-
this suppression of Aβ production by caffeine occurs at feine treatment, however, these same mice exhibited a
physiologic concentrations (1–10 µM) – caffeine con- restoration of working memory to the level of normal,
centrations that are present in the plasma and brain fol- aged mice [12]. In these same aged Tg mice, which
lowing only 1–2 cups of coffee. Parenthetically, we are had substantial brain Aβ deposition prior to caffeine
not aware of any AD drug under development by the treatment, reductions of 40% and above for both sol-
pharmaceutical industry that has caffeine’s profound uble and deposited (insoluble) brain Aβ were evident
ability to reduce both Aβ − producing enzymes. As following caffeine treatment [12].
depicted in Fig. 1, “unmodified” brain Aβ production The profound cognitive restoration by caffeine in
and aggregation during aging in Tg mice inevitably re- aged AD mice is likely due to caffeine’s aforemen-
sults in memory impairment. By contrast, long-term tioned ability to reduce Aβ production by reducing both
(“life-long”) caffeine intake to Tg mice reduces brain β- and γ-secretase protein expression [11]. We have
Aβ production/aggregation, thus protecting against de- further extended these mechanistic findings by showing
that 1) caffeine administration to Tg mice was able to
velopment of Aβ-induced memory impairment (Fig. 1).
reduce the Raf-1/NFκB inflammatory pathway, which
stimulates brain β-secretase, and 2) caffeine suppress-
Caffeine to treat Alzheimer’s disease: transgenic es both α and β isoforms of GSK-3 in neuronal cell
mouse studies cultures, which are linked to PS1/γ-secretase activity
and tau hyperphosphorylation, respectively. Regard-
To determine if caffeine treatment has the ability ing suppression of the Raf-1 inflammatory pathway, we
to reduce pre-existing memory impairment and Aβ have determined that caffeine stimulates PKA activity
neuropathology, caffeine treatment in drinking water in the hippocampus of treated AD Tg mice [12]. This
(300 mg/L) was administered for 2 months to “aged” enhanced PKA activity then inhibits (inactivate) cRaf-
Tg mice already exhibiting both of these AD character- 1 by phosphorylation at serine259, decreasing NFκB
istics [12]. This concentration of caffeine in drinking activity and the expression of NFκB-controlled genes
water, which is identical to that utilized in our prior such as BACE1, thus resulting in decreased Aβ pro-
S120 G.W. Arendash and C. Cao / Caffeine and Coffee as Therapeutics Against AD
duction. Regarding the suppression of GSK-3, caffeine the antioxidant actions of caffeine [15], its ability to
affects both active and holoprotein (total) GSK-3 lev- block disruptions of the blood-brain barrier [16], and its
els [12], which suggests that caffeine does not dimin- well-established antagonism of brain A1 and/or A2A
ish GSK-3 activity through direct substrate-level phos- adenosine receptors [1,2,17,18]. Regarding the latter,
phorylation, but rather through alternations in protein adenosine receptor antagonism may be central to most
production or degradation The extent to which either or or all of the beneficial actions of caffeine against AD.
both of these caffeine mechanisms involve adenosine Any combination of such mechanisms of caffeine ac-
receptor antagonism is unknown and currently being tion may collectively provide the cognitive benefits we
investigated. have documented in AD mice.
Our measurement of plasma caffeine levels of The effects of caffeine on established AD charac-
aged, behaviorally-evaluated AβPPsw mice given two teristics are summarized in Fig. 1 (Caffeine after AD),
months of caffeine treatment underscores the human which shows caffeine-induced suppression of Aβ pro-
relevance and physiologic significance of the caffeine duction leading to removal of Aβ from the brain,
treatment in this long-term study. At the caffeine con- resulting in reversal of cognitive impairment. This
centration in drinking water that was employed, plasma study [12], performed in aged AD mice, provides the
caffeine levels averaged 26 µM [13], equivalent to the first evidence that caffeine treatment can reverse cog-
plasma caffeine concentration expected in humans fol- nitive impairment and AD neuropathology in a model
lowing intake of several cups of coffee. This caffeine for the disease.
concentration is very close to the 20 µM concentration
that we found to be optimal in our cell culture studies Theophylline and cognitive function in AD transgenic
for suppression of Aβ 1−40 and Aβ1−42 production, al- mice
though caffeine concentrations in the much lower nM
range (250–500 nM caffeine) were also effective [11]. As a major active metabolite of caffeine, theo-
This very low nM range of caffeine effectiveness to phylline may be responsible for a significant part of
reduce Aβ production in vitro is below the level of any the cognitive benefits we found through long-term caf-
known molecular target, including adenosine receptor feine administration. In the aged Tg mouse study just
antagonism. As such, caffeine’s reduction of Aβ pro- presented [12,13], we found plasma theophylline levels
duction appears to be novel in being independent of to be strongly correlated with plasma caffeine levels.
adenosine receptors actions. It is important to note that Moreover, theophylline has a longer half-life than caf-
theophylline, one of several active metabolites of caf- feine, with brain concentrations of theophylline usual-
feine, may be responsible for at least some of the cog- ly being higher than those for caffeine following long-
nitive, neuropathologic, and neurochemical benefits of term caffeine treatment [19]. Thus, it is important to
caffeine. This premise is underscored by the fact that determine the extent to which theophylline, contributes
caffeine metabolites such as theophylline have a con- to the cognitive benefit we are attributing to caffeine
siderably longer half-life than caffeine. We have ex- administration in our AD mice. We therefore admin-
plored the contribution of theophylline to the benefits istered theophylline in drinking water (200 mg/L) to
currently being attributed to caffeine in our AD mice, AβPPsw+PS1 double transgenic mice (Jackson Lab-
and report our findings in the next section. oratories, Bar Harbor, Maine) or non-transgenic lit-
Also in this long-term caffeine treatment study in termates beginning at 5.5 months of age. The re-
aged AD mice, we found a clear reduction in hip- sulting dose of theophylline (approximately 1 mg/day)
pocampal inflammatory cytokines in caffeine-treated is just slightly less than the 1.5 mg/day dose of caf-
mice with higher plasma caffeine levels compared to feine we routinely administer long-term to AD mice.
those with lower caffeine levels. The ability of caf- This theophylline dosage presumably resulted in plas-
feine to provide beneficial anti-inflammatory effects in ma theophylline levels at least as high as those result-
the brains of AD mice is consistent with prior studies ing from chronic caffeine administration because AD
supportive of its anti-inflammatory capacities [14] and, mice chronically treated with caffeine have a plasma
as such, could represent a potent “non-amyloidogenic” caffeine-to-theophylline ratio of approximately 8-to-
mechanism of caffeine action that may contribute to 1 [13].
its ability to protect against/reverse cognitive impair- At 6 months into theophylline treatment, mice were
ment. Other beneficial mechanisms of caffeine ac- evaluated in our standard 6-week behavioral battery
tion in AD mice (and perhaps in human AD) include of sensorimotor, anxiety, and cognitive-based tasks, as
G.W. Arendash and C. Cao / Caffeine and Coffee as Therapeutics Against AD S121
Fig. 2. Inability of long-term treatment with the active caffeine metabolite theophylline to provide cognitive benefit to AD transgenic mice or
non-transgenic littermates, as demonstrated by the radial arm water maze task of working memory. The data presented are for Trial 1 (naı̈ve
first trial), and Trials 4 and 5 (working memory trials) overall across 12 days of testing at 6 months into theophylline treatment. The number of
animals in each group were: NT controls (n = 7), NT+theophylline (n = 8), Tg controls (n = 7), and Tg+theophylline (n = 9).
done in our initial caffeine study [11]. Across multiple the cognitive benefits of caffeine administration in our
cognitive-based tasks [Y-maze spontaneous alternation, prior protection-based [11] and treatment-based [12]
Morris maze acquisition/retention, circular platform, studies were likely due to caffeine itself, and not theo-
platform recognition, and radial arm water maze], there phylline. Whether or not the other major caffeine
were no effects of theophylline treatment in either Tg metabolite (paraxanthine) may be responsible for some
or non-transgenic mice compared to controls. An ex- of caffeine’s cognitive benefits in Tg mice remains to
ample of this surprising lack of cognitive benefit with be determined.
long-term theophylline treatment is shown in Fig. 2 for It is important to put our long-term theophylline
the radial arm water maze task of working memory. treatment study (> 7 months of treatment) in proper
For both errors and latency during working memory context of prior work investigating theophylline’s ef-
trials T4 and T5, theophylline-treated mice performed fects on cognitive function. Our search of the scien-
no different from controls across 12 days of testing. In tific literature has, firstly, revealed a wealth of stud-
addition, there were no effects of theophylline treat- ies showing no effect of theophylline administration on
ment on sensorimotor tasks (open field activity, balance the cognitive performance of humans (both adults and
beam, string agility) or on the elevated plus-maze task children). This is consistent with our present finding of
of anxiety (data not shown). Thus, we conclude that long-term theophylline treatment having no cognitive
S122 G.W. Arendash and C. Cao / Caffeine and Coffee as Therapeutics Against AD
Fig. 3. Brain Aβ production/clearance, the suppressive actions of caffeine on Aβ production, and resultant effects on brain and plasma Aβ
levels. (A) Unmodulated: Aβ is primarily produced in neurons, secreted into the brain extracellular space in soluble form, then enters a dynamic
equilibrium between soluble and deposited (insoluble) Aβ. Continual transport of soluble Aβ occurs into plasma. (B) Caffeine: Short-Term:
Caffeine suppression of both β- and γ-secretase activities reduces Aβ production, resulting in lower soluble Aβ in brain and plasma. The
equilibrium between soluble and deposited Aβ is not impacted by this short-term reduction in brain soluble Aβ levels. (C) Caffeine: Long-Term:
Continuous caffeine suppression of Aβ production and resultant chronically lower levels of brain soluble Aβ induce a flux of deposited (insoluble)
Aβ to the soluble form, which is cleared from brain into plasma via soluble Aβ transport. Plasma Aβ levels may be reduced or not changed,
depending on degree of caffeine-induced suppression of Aβ production. Reproduced with permission from IOS Pres.
effects in normal mice across multiple tasks and cogni- both β- and γ-secretase [11,12], we have hypothesized
tive domains. Secondly, no studies had investigated the that ensuing lower brain levels of soluble Aβ will result
effects of “long-term” theophylline on cognitive func- in lower plasma Aβ levels acutely (Fig. 3B). This hy-
tion prior to our present work. Earlier studies only in- pothesis is supported by the finding that Aβ is rapidly
volved “acute/single treatment” theophylline adminis- produced and cleared from the brain [20]. Moreover,
tration to normal mice or as a pre-treatment to mice ex- following almost 2 months of caffeine administration
posed to a noxious stimulus (e.g., ischemia, microwave to “aged” Tg transgenic mice (see preceding section),
irradiation). Particularly since acute administration of we have found that higher plasma caffeine levels were
caffeine (and presumably theophylline) may have cog- strongly associated with lower plasma Aβ levels in in-
nitive effects that are different from long-term adminis- dividual Tg mice (r = −0.761; p = 0.011).
tration, the behaviorally-based theophylline study that Considering the above findings, we determined the
we present in the current manuscript appears to be the effects of acute caffeine [13] or coffee administra-
first long-term theophylline treatment study investigat- tion on plasma and brain Aβ levels in AD transgenic
ing cognitive performance in any rodent, either normal, mice. Acute (single treatment) administration of caf-
genetically-manipulated, or CNS-injured. feine (1.5 mg/0.2 cc) or saline vehicle was given by
i.p. injection or gavage to AβPPsw transgenic (Tg)
Acute effects of caffeine/coffee on blood Aβ levels in mice in young adulthood (3 months old) or in older age
AD mice and humans (14 months old). At 3 hours following treatment, plas-
ma Aβ1−40 levels in 3-month old Tg mice were sub-
Following formation of monomeric Aβ in the brain, stantially reduced by 41%. Even the older 14-month
newly produced Aβ enters into a dynamic equilibrium old Tg mice showed significant reductions in plasma
between soluble and deposited Aβ in the brain, with Aβ following acute caffeine treatment. We have since
continual transport of soluble Aβ out of the brain and repeated these studies in additional Tg mice, acutely
into plasma down a concentration gradient (Fig. 3A). administering caffeinated or de-caffeinated coffee (i.p.)
Therefore, blood levels of Aβ may be indicative of caf- instead of caffeine (Caffeinated coffee contained the
feine’s therapeutic actions on brain levels of Aβ. In same 1.5 mg caffeine/0.2 cc as in pure caffeine admin-
view of our findings that caffeine decreases Aβ pro- istration). At 3 hours following an initial treatment and
duction in AD transgenic mice through suppression of 3 hours after another treatment 3 days later, caffeinated
G.W. Arendash and C. Cao / Caffeine and Coffee as Therapeutics Against AD S123
sumption level) are needed to reach the 500 mg level, If the inability of long-term theophylline adminis-
while many more servings of tea or soft drinks would tration to mimic the therapeutic effects of caffeine is
be required. Moreover, given coffee’s significant con- independent of the AD mice and treatment paradigm
tent of antioxidants and other beneficial phytochemi- utilized (as we suspect is the case), this would argue for
cals, this source of caffeine is clearly preferable over such benefits of caffeine to be independent of adenosine
essentially any other source. receptors. Supportive of this premise, theophylline is 3
Caffeine’s beneficial effects against cognitive im- to 5 times more potent than caffeine as an antagonist of
pairment and AD neuropathology probably involve first both adenosine A1 and A2a receptors. Alternatively,
and foremost the unique ability of caffeine to suppress it is possible that brain theophylline levels (which we
both enzymes needed for brain Aβ generation, name- did not measure in this study) in theophylline-treated
ly β-secretase and γ-secretase. Nonetheless, multiple Tg mice were insufficient for providing behavioral and
other mechanisms are probably contributing to the ther- neuropathologic benefit. Either scenario would be con-
apeutic actions of caffeine in AD animal models, in- sistent with a mechanism that does not primarily in-
cluding caffeine’s ability to act as: 1) a strong anti- volve adenosine receptor antagonism.
inflammatory agent, 2) an anti-oxidant, 3) a mitochon- In our ‘acute” studies, AD mice given a single
drial activator, and 4) a stimulator of both neuronal ac- treatment with caffeine exhibited quick reductions in
tivity and glucose utilization. Although adenosine re- both brain interstitial fluid and plasma Aβ levels (i.e.,
ceptor antagonism should certainly be included in this within 2–3 hours). Since caffeine did not affect
list, caffeine’s actions almost certainly do not involve the half-life of ISF Aβ, caffeine had directly affect-
simply the increase in alertness provided by such recep- ed brain Aβ production rather than its elimination.
tor blockade. Indeed, if this were a primary mechanism Underscoring this premise are our findings that caf-
of caffeine’s cognitive benefit, normal mice should have feine affects Aβ production through suppression of
benefited cognitively from a lifetime of caffeine ad- both β-secretase (BACE1) and γ-secretase/PS1 expres-
ministration, but this was not the case [12]. Thus, we sion [11,12]. Acutely, this caffeine-induced decrease
propose that caffeine does not act as a general nootrop- in Aβ production would result in lower soluble Aβ in
ic agent to enhance “normal” cognitive performance. brain ISF and consequently lower plasma Aβ levels
Rather, we believe that caffeine protects against and (Fig. 2, Caffeine – Short-Term). This is exactly what
minimizes brain cognitive impairment, such as that due we observed in AD mice that were young adults (with
to brain Aβ accumulation/aggregation in AD. no brain Aβ deposition), as well as aged AD mice
Studies in this paper present evidence that caffeine (bearing robust Aβ deposition). Whether or not this
is providing cognitive benefits to AD transgenic mice caffeine-induced suppression of Aβ production is di-
directly, since a major active metabolite of caffeine rect or involves adenosine receptor blockade/mediation
(theophylline) was found to be cognitively ineffective. is currently unknown. Evidence against involvement
It is important to note, however, that our theophylline of adenosine receptors is provided by studies showing
administration studies utilized mice of a different trans- that acute and chronic caffeine administration to mice
genic line (AβPPsw + PS1), bearing a different strain given noxious brain conditions (e.g., ischemia, exci-
background (C57/BL6), and obtained from a commer- totoxin exposure) results in opposite effects (worse or
cial breeder (Jackson Laboratories). By contrast, all lesser damage) due to antagonism of A1 and A2a re-
of our other behavioral studies with caffeine adminis- ceptors, respectively [21]. In sharp contrast, both acute
tration [11–13] involved inbred mice of our own trans- and chronic caffeine administration decrease plasma
genic colonies. We have previously determined that and brain Aβ levels.
AβPPsw or AβPPsw + PS1 mice on a C57/BL6 back- In our long-term “treatment” study in aged/cognitive-
ground (e.g., those from commercial breeders) require ly-impaired AD mice, caffeine reversed their working
considerably longer aging (compared to our inbred memory impairment. This 2-month caffeine adminis-
mice on a mixed C57/BL6/SW/SJL background) be- tration regime not only reduced brain soluble Aβ levels,
fore cognitive impairment becomes apparent. Thus, but also reversed brain Aβ neuropathology. Although
it is possible that results of this study could have the mechanism(s) for caffeine-induced reversal of Aβ
been different had we utilized mice of our own inbred deposition requires further investigation, we hypothe-
colonies and/or began the study with aged, already- size that “chronic” caffeine suppresses Aβ production
impaired transgenic mice for examining the effects of long-term, resulting in consistently lower brain levels
theophylline administration on cognitive function. of soluble ISF Aβ (Fig. 2, Caffeine – Long-Term). This
G.W. Arendash and C. Cao / Caffeine and Coffee as Therapeutics Against AD S125
would then induce a flux of insoluble Aβ out of the In summary, our studies utilized AD transgenic mice
deposited form and into the soluble form due to dy- to demonstrate that: 1) Caffeine protects AD mice
namic equilibrium. Newly-solubilized Aβ would then against memory loss through mechanisms that directly
be cleared into the plasma via both blood-brain-barrier affect the disease process, 2) Caffeine reverses mem-
transport and bulk fluid flow. The dynamic equilibri- ory loss and AD pathology in “aged” AD mice, and
um between soluble (ISF) and insoluble/deposited Aβ 3) Caffeine and/or caffeinated coffee both affect plas-
in the brain is underscored by previous work showing ma levels of Aβ in AD mice and humans. Our results
that young adult and aged AβPPsw mice had similar warrant the clinical trials in progress with caffeine and
steady-state levels of ISF Aβ, but rapid inhibition of Aβ caffeinated coffee as safe, inexpensive, and effective
production resulted in a two-fold longer Aβ half-life therapeutics against AD.
in the aged, Aβ deposit-bearing mice [22]. We believe
this longer Aβ half-life is caused by solubilization of
a portion of the deposited Aβ pool due to the dynamic
ISF Aβ ↔ deposited Aβ equilibrium. ACKNOWLEDGMENTS
The effects of “chronic” caffeine intake on health
have been reported in numerous retrospective and The following collaborators in these studies are
prospective studies. A comprehensive review of the gratefully acknowledged: Valentina Echeverria, John
literature [23] found that for healthy adults, moderate Cirrito, David Holtzman, Huntington Potter, Takashi
daily caffeine intake poses no adverse effects on the Mori, Maggie Mamcarz, Melissa Runsfeldt, Li Wang,
cardiovascular system, bone status and calcium bal- William Schleif, Edwin Jackson, Jennifer Cracchiolo,
ance, or incidence of cancer. Prospective studies have Daniel Shippy, Alexander Dickson, Ashok Raj, Kavon
not found significant associations between coffee con- Rezia-Zadeh, Jun Tan, Bruce Citron, Xiaoyang Lin,
sumption and the risk of coronary heart disease [24, and Chi Zhang. This work was supported by NIH grant
25]. Contrary to public belief, caffeine intake of 500– AG025711 and funds from the Byrd Alzheimer’s Cen-
600 mg daily does not increase the risk, frequency, or ter and Research Institute.
severity of cardiac arrhythmias [26,27]. Indeed, there Authors’ disclosures available online (http://www.j-
is a growing list of age-related diseases wherein habit- alz.com/disclosures/view.php?id=242).
ual caffeine intake of 400–600 mg (4–6 cups of coffee)
daily reduces the risk. For example, strong data from a
number of prospective studies show that both caffeine
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