Doença de Alzheimer

Profa. Marcela
B. Echeverry
1
 Churchill, Roosevelt e Stalin
Conferência de Yalta e Potsdam
 HISTÓRIA
Conheceu o colega
Franz Nissl e por
meio do método de
Nissl descreve as
modificações nas
camadas neuronais
corticais que
Aloysius Alois acompanham a
Alzheimer
Auguste Deter doença de Alzheimer,
sendo visualizada na
paciente Auguste
Deter em 1906,
quando analisa o
cérebro dela
 DEFINIÇÃO
◼Prevalência 5% após 65 anos e cerca de 90% aos 95 anos
◼Progressão Gradual ao longo do envelhecimento
◼Perda da memória recente, de habilidades visual-espaciais, de
cálculo e de uso de objetos e ferramentas comuns
◼Morte ocorre após 6 - 15 anos após início da doença
◼Diagnóstico definitivo post-mortem:
– Atrofia do córtex cerebral, perda de neurônios corticais e
sub-corticais
– Achados Patológicos: placas senis (A) e emaranhados
neurofibrilares ( - fosforilada) c/ processos degenerativos
– Depósitos abundantes no hipocampo e regiões do córtex
associativo (exceto visual e motor)
◼ ACh / envolve também sistemas de outros neurotransmissores
Doença de Alzheimer
Lobos mais comprometidos
 Lobos mais comprometidos

Atrofia de áreas da memória, linguagem, gyrus, e aumento de

tamanho dos sulcos e ventrículos (lateral e 3er ventrículo)
 7 Stages of Alzheimerʼs disease

1 – No impairment
2 – Normal aged forgetfulness
3 – Mild cognitive impairment
4 – Mild Alzheimerʼs
5 – Moderate Alzheimerʼs disease
6 – Moderately severe Alzheimerʼs
disease
7 – Severe Alzheimerʼs disease
criteria set by the National Institute of Neurological and Communicative Disorders
and Stroke and the Alzheimer’s Disease and Related Disorders Association
(NINCDS/ADRDA)
Hypothetical scenarios for the onset of
Alzheimerʼs disease
Alzheimer’s Disease Is a Synaptic
Failure?
 The neuropsychological profiles of dementia reflect the
impact of disease on distinctive neuroanatomic networks
associated with complex cognitive domains

Perisylvian area, site

of many language
functions

Cold Spring Harb Perspect Med 2012;2:a006171

 TREATMENT
• acetylcholinesterase inhibitors (Donepezil), delays
deterioration of memory and attention -studies demonstrate
that the therapeutic response in AD is genotype-specific -
metabolized via CYP-related enzymes, especially CYP2D6:
genotypes CYP2D6*1/*10 and *10/*10 were found in
responders (than those with CYP2D6*1/*1 genotype) - mutant
allele (*10) in CYP2D6 gene may respond better to donepezil
(Am J Med Sci. 2013 Mar;345(3):222-6)

• Memantine: low to moderate affinity NMDAR antagonist -

patients with mild to moderate AD – on cognition and
neuropsychiatric functioning.

• memory training, mental and social stimulation, and physical

exercise programs -aim to delay the loss of mental abilities, to
help people stay independent in everyday - Occupational
therapy
• Deep Brain Stimulation(DBS) – experimental study – Mild
Alzheimer
 • Appear between the
ages of 40 and 65
• Usually does not
Frontal lobes include formation of
amyloid plaques
• Exhibit impolite and
socially inappropriate
behavior
• Can is linked to a
mutation in the tau
Temporal lobes
gene (FTDP-17,
Frontotemporal dementia
Parietal lobe Parietal lobe
with parkinsonism-17);
N279K, ΔK280,
P301L, P301S,
Temporal
lobe V337 and R406W
(Götz & Ittner, 2008)

Temporal
lobe
Miller & Lee, 2006
 "Cholinergic Hypothesis“ - "Amyloid Hypothesis"
Ashford (J Alzheimers Dis. 2015)

The most severe neuropathological changes occur in the

hippocampus, followed by the association cortices and subcortical
structures, including the amygdala and nucleus basalis of Meynert

Arnold et al (Cereb. Cortex, 1991)

 "Cholinergic Hypothesis“ - "Amyloid Hypothesis"
Ashford (J Alzheimers Dis. 2015)

Cholinergic cells of dorsal tegmental area Ch5,

Ch6, Ch8 are cells forming the ascending reticular
activation system.
PPN: pedúnculo pontino Source: Eric J Nestler www.neurology.mhmedical.com
Normal Alzheimer
A B C

Neurofibrillary
tangles

Cedida por M. Palacios, 2014

 A
C
Marcação para tau-patologia
A –emaranhados neurofibrilares
B – placas neuríticas
C – neurofilamentos truncados

nicholas.kanaan@hc.msu.edu
 FATORES DE RISCO
• Idade.
• Genética: 1%, autosómica dominante, mutações em três
genes: APP, Presenilina (PSEN1) e (PSEN2). Presenilina é
componente do complexo γ-secretase, que junto com β-
secretase geram proteína Aβ
Genes relacionados com Tau: MAPT, ligado ao
cromossomo 17, relacionado com Demência Fronto-
temporal com parkinsonismo
• DA esporádica: Metabolismo (colesterol, diabetes,
Homocisteina), APOE (APOE4)
• Doença cerebro vascular.
• Traumatismo craniano grave.
 Patients with
Alzheimer's can live
from 2 to 15 years
from diagnosis
© 1996-2015 MedicineNet.
All rights reserved Leclerc & Abulrob, 2013

chronic and
progressive nature
• cognitive decline in
humans is not
proportional to Ab
plaque load (Terry et
al. 1991)
• correlate with soluble
Ab species (Wang et
al. 1999)
http://www.humpath.com/spip.php?article13103
 • Os neurônios aumentam quando ativos
e encolhem quando dormentes.
Portanto, o tamanho do espaço entre eles
é alterado.
• Durante o sono, os neurônios encolhem
drasticamente para permitir aumento do
ECS (até um 60%) com um aumento do
fluxo de fluido pelo espaço permitindo
intercambio entre fluído cérebro-
Vermelho é aumento do ECS
espinhal com o intersticial, permitindo
restaurar funções fisiológicas como
limpar a β-amiloide

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880190/
 ECS

ECS
AQP4: aquaporim 4, é um proteína canal
prevalente perto dos astrócitos e membrana
dos vasos sanguineos permitindo a saída de Sistema linfático
água

O conjunto “glymphatic” (glia +

linfático) limpam os “detritos” neuronais
 APP processing:
Aβ40
diffusible oligomeric
↑BACE1 Aβ42
assemblies of the
amyloid protein
Aβ42 the more fibrillogenic and
Presenilin - PSEN 1 and 2, neurotoxic species
nicastrin
cdk5
GSK3

tau phosphorylation

Cdk5: Cyclin-dependent kinase 5

GSK: Glycogen synthase kinase-3

Götz & Ittner, 2008
Natural Compounds That Modulate BACE1-processing of Amyloid-
beta Precursor Protein in Alzheimer’s Disease

Dropping the BACE:

Beta Secretase
(BACE1) as an
Alzheimer’s Disease
Intervention Target
 PROTEÍNA GSK3

Glycogen synthase kinase-3

http://www.genscript.com/alzheimer's_disease_antibodies.html
Cdk5: Cyclin-dependent kinase 5
anterior pharynx-defective 1 (APH1)
 Glycogen synthase kinase-3

http://journal.frontiersin.org/Journal/10.3389/fnmol.
2011.00016/full

http://www.anti-agingfirewalls.com/2014/09/30/the-alpha-and-
beta-of-gsk-3s-first-in-the-strange-but-powerful-molecules-series/
 epigenetically
regulated
TTR
el dominio intracelular
de APP (AICD).

NEP: Neprisilina
TTR: transtiretina

Abeta-clearance protein transthyretin (TTR), Kerrigne et al., 2014J

Neprilysin (NEP) Neurochem. 2014.
 Future perspectives

• Simultaneous up-regulation of NEP

and TTR gene expression might
provide a platform for designing a
strategy towards enhancement of
amyloid clearance in the ageing
brain via different mechanisms.
 Transgenic mouse models of
dementia
• familial forms of AD and FTD
• genes that encode the proteins that
are deposited in plaques (APP)
• genes that encode tau, in AD and
FTD (MAPT)
 Götz & Ittner, 2008
FTD
* *
FAD FTD

prolyl isomerase Pin1

glycogen synthase kinase-3β
Ling Ma, et al., 2012; Terwel et al., 2008;
Phiel et al., 2003
 Transgenic mouse models of
dementia
• ApoE models: lentiviral delivery of ApoE4 in ApoE-/-
increased Aβ formation (Dodard et al., 2005)

Anti-oxidant
α-tocopherol
Stressor: (vitamin E)
-impaired energy
metabolism,
-mitochondrial
dysfunction,
-chronic oxidative
stress,
-cerebrovascular Oxidative
disease/cerebral stress
hypoperfusion
 represses • low-density lipoprotein
NMDAR
activity
receptor (LDLR)-
related proteins (LRP),
• APOER2, APOE
receptor 2;
• DAB1, disabled 1;
• GSK3b;, gylcogen
synthase kinase 3;
promoting the • PKB, protein kinase B
endocytosis of
NMDARs
(Akt);
• SFKs, SRC family
results in tyrosine kinases;
elevated
phosphorylation
• VLDLR, very-low-
density lipoprotein
receptor.
Reduced glutamatergic transmission
could result in impaired synaptic
plasticity and promote neuronal loss and
dementia
http://www.humpath.com/spip.php?article13103
ApoE, ApoE receptors, and the
Synapse in Alzheimer’s Disease
 Metaplasticidade e ECS
• Metaplasticidade: forma de plasticidade sináptica
persistente; LTP ou LTD (long-term potentiation or
depression)(https://www.ncbi.nlm.nih.gov/pubmed/8658594)
Pode envolver receptores NMDA e AMPA de glutamato
• De dentro da célula, o aumento
de cálcio desencadeia a
plasticidade sináptica. Reelina,
fora da célula, regula os
receptores críticos de
glutamato NMDA. Ela ajuda na
migração de neurônios e
formação do córtex e do córtex
cerebelar controlando a ordem
de chegada das células para
Estimula
actina formar as camadas. Reelina
continua a ser um fator crítico
na função das sinapses.
Grande conclusão: que LTP e LTD -VLDLR : very-low-density-lipoprotein receptor
também depende de um receptor de -APOER2: apolipoproteína E receptor 2 – RECEPTOR DE
REELINA
reelina -LVDCC: L-type voltage-dependent Ca2+ channel
 Focusing on stress
response and
inflammation

Aisen PS, 2002

Vasto et al., 2007
The impairment of insulin
signaling in Alzheimer's
disease
(Candeias et al., 2012)
PI3K: fosfatidilinositol 3-kinase
Akt: serina-treonina kinasa - PKB, protein-
kinase B
IDE: insulin-degrading enzyme
Insulin resistance lowers the expression
of insulin-degrading enzyme (IDE).
IRS: insulin receptor substrate ↑levels of α and β-tubulina
Astrocyte - Glucose (GLUT1 and 3) - Glutamate Reuptake

GLUT 3

Glutamina
sintetase
GLUT 1

Source: Stuart Ira Fox – www.accesmedicina.com

 amyloid beta-derived diffusible ligands
amyloid beta-derived diffusible ligands (ADDLs)
Biochem Pharmacol. 2013 Dec 28. doi:10.1016/j.bcp.2013.12.012.
J Alzheimers Dis. 2005;7:63-80.
amyloid beta-derived diffusible
ligands (ADDLs)

Najem et al., 2014-03-13 | DOI: https://doi.org/10.1515/revneuro-2013-0050

 Mitochondria are dynamic organelles that are
essential for cellular metabolism but can be
functionally disrupted during pathogen infection

Kramer and Enquist, 2012

Alphaherpesvirus infection disrupts mitochondrial transport in neurons
doi: 10.1016/j.chom.2012.03.005
 Fatores tróficos: Proteínas relacionadas à atividade antiapoptótica, uma vez que na
sua ausência a proteína BAD pode promover a apoptose. Ex:. NGF- factor de
crecimiento nervioso; IGF: factor de crecimiento insulínico

Apaf: Apoptosis protease activating factor-1 e 2 LODISH, et al., MOLECULAR CELL BIOLOGY, Fifth Edition
 MRI

• Type 2 diabetes Mellitus (TIIDM):

reduced hippocampal volume and
partial atrophy of the amygdala -
directly related to decreased
memory
Musen, G., Lyoo, I.K., et al. (2006)
Knight, S., Nostham, E., et al. (2009)
Den Heijer, T., Vermeer, S.E., et al. (2003)
• Also greater risk of emerging
depression
Multifunctional role of astrocytes as gatekeepers of
neuronal energy supply

The Astrocyte to Neuron

Lactate Shuttle
Hypothesis

phosphate- production
activated through
glutaminase glutamate
uptake

astrocytic
glutamate
transporters

Front. Cell. Neurosci., 10 April 2013 | https://doi.org/10.3389/fncel.2013.00038

Astrocyte intracellular Ca2+ elevations trigger
release of vasoactive molecules

cytochrome P450
epoxygenase

AA: arachidonic acid

EET: epoxyeicosatrienoic acids
Front. Cell. Neurosci., 10 April 2013 | https://doi.org/10.3389/fncel.2013.00038
MCT: monocarboxylate transporters - Lactate transport
Sporadic Alzheimer’s disease - Animal model

Modificado de Inestrosa et al., Brain Pathology 2015

Pathways – non canonical effects

Adult hippocampal Child obesity: early

neurogenesis impacts on the CNS
 Tratamentos aprovados para a DA

¨ Anticolinesterásicos
· galantamina
· rivostigmina
· donepezila

¨ Inibidores do NMDA
· memantina

¨ Fitoterápicos
· Ginkgo biloba
OBRIGADA!