9/28 Alzheimer's Disease - Matise Flashcards
dementia
loss of cognitive fx
- not a disease; group of sx that may accompany certain diseases or conds
- changes in personality, mood, behavior
- memory loss
- irreversible when caused by disease/injury, potentially refersible if caused by drugs/alc/hormone_vit imbalance/depression
four major neurodegen dementias
- Alzheimer’s disease
- frontotemporal demential (formerly: Pick’s disease)
- dementia with Lewy bodies
- Creutzfeld-Jakob
common features of dementia syndromes
- begin in pre-senescence
- both genetic and sporadic forms
- involve abnormal protein aggregation in neural tissue → disrupts neuronal fx
- AD: amyloid beta42
- frontotep demential: tau (also AD!)
- dementia with Lewy: alpha-synuclein
- CrJ: prion
***genetic forms are caused by mutations in genes that code for/affect fx of a protein
- there are susceptibility genes for each which increase the likelihood of developing disease
sporadic forms of disease: risk factors
no single genetic abnormality is causative for disease
non-genetic risk factors can lead to accelerated synapse loss
- head trauma
- stroke
- HTN
- DM
- high chol
- low exercise
- elevated homoCys
- age
many of these can be reduced by behavioral mods
neuropathology of Alzheimer’s Disease
- presence of neuritic plaques and tangles
-
synaptic and neuronal loss due to apoptosis
- reduced brain volume due to atrophy
clinical features of AD
most common age-related degen demential (2/3 of all cases)
- usually starts with gradual failure of recent/episodic memory
- alertness and motor fx spared
- anosmia! (recall: connection to neurogen happening in those cells)
patients typically die within 5-9 years following onset
AD and age
AGE is the MAJOR RISK FACTOR for AD
- most cases are sporadic
onset of sx usually after 65-70yo
- risk for developing AD doubles every 5 years after 65
- after 85, prevalence is 40%
- onset before 60: “pre-senile”, approx 1%. typically inherited, referred to as familial AD
neuritic plaques
neuritic plaques contain extracellular deposits of insoluble fibrils (polymers of amyloid beta-protein, A-beta42)
inflammatory response in response to neuritic plaques: cytokines produced by astrocytes/microglial cells
amyloid beta-protein
- how does it form?
- how does the brain attempt to clear it out?
formation: amyloid beta is product of normal processing of amyloid precursor protein (APP, longer transmembrane protein…don’t know the fx of it)
- APP is cleaved constitutively by alphaSecretase and betaSecretase
- products of each cleavage further cleaved by gammaSecretase
amyloid_beta protein family is product of cleavage by 1. BACE (beta-site APP Cleavage Enzyme) & 2. gammaSecretase
- family comprises 40 and 42 a.a. proteins
- produced normally throughout life
- no clear fx
- normal ratio of 40:42:x is 70:15:15 → normally not that many 42s!
common parlance:
- betaSecretase pathway = pro-amyloidogenic
- alphaSecretase pathway = anti-amyloidogenic
“amyloid hypothesis”
post-morten studies of AD patients show that neuritic plaques are comprised primarily of 42aa form of amyloid beta protein
→→→hypothesis: Abeta42 is the causative agent of AD!
- extracellular accumulation of insoluble Abeta42 disrupts neuronal and synaptic fx → cell death
evidence for amyloid hypothesis
mouse models
transgenic mice overexpressing mutant forms of APP and tau → formation of amyloid plaques and neurofibrillary tangles
- extracellular plaques that are forms ONLY show Abeta42 (not Abeta40)
- conclusion: Abeta42 is more prone to aggregation
genetic evidence for amyloid hypothesis
- adults with Down Syndrome (trisomy 21) develop early onset AD (approx age 40)
* APP gene is on chr21 → trisomy 21 pts hve increased APP gene dosage → incr Abeta42 production - mutations that favor excessive production/deposition of Abeta42 also cause dominantly inherited AD
- Presenilin1 (chr14) → incr produc of Abeta42
- Presenilin2 (chr1) → incr produc of Abeta42
- mutations that reduce production/deposition of Abeta42 associated with protective effect against AD!
role of apoE
apoE fx:
- involved in chol/lipid transport
- possibly involved in cell membrane repair
three alleles (E2, E3, E4), with E4 increasing risk of developing AD
- apoE4 allele produces a protein that is less stable than the other alleles
- apoE4 protein also…
- impairs Abeta42 clearance (promotes aggregation)
- promotes tau hyperphos
role of Presenilin
gain of fx mutations in Presinilin → assoc with familial AD
- Presinilin (PS1, PS2) are part of gammaSecretase complex resp for production of Abeta42 from APP
evidence: mice with mutations in PS1 (incr in stability/activity) → accel amyloid deposition in entorhinal cortex
other genes linked to sporadic AD
- clusterin/apolipoproteinJ
- CR1
- PICALM
clusterin/apolipoprotein J
- similar to apoE4
- regulates Abeta42 aggregation, deposition
CR1
- complement-related protein w possible role in Abeta42 clearance
PICALM
- involved in endocytosis
- may regulate APP trafficking in cells
graphical summary of production of Abeta42 and involved genetic factors
amyloid hypothesis:
plaques vs oligomers
conflicting evidence
once upon a time, plaques and AD were synonymous with one another
contradictory evidence:
- some patients diagnosed with AD do not show plaques in postmortem study!
- some patients with plaques have no signs of AD
- reduction in plaque load via ab immunotx → no improvement in memory fx (inconclusive)
- mouse models of AD show memory deficit prior to plaque formation
Abeta42 oligomer toxicity
why might oligos be worse than plaques??
oligomer formation is an intermediate step on the way to plaque formation
- overproduction of Abeta overproduction of reduced clearance → soluble oligomers
- oligomers → synapto/neurotox
- smaller size gives them more mobility/ability to bind to receptors
- potentially more dangerous than larger aggregate plaques (theory: plaques are to big to be able to affect specific fx → relatively benign that that stage/size)
LilrB2 and oligomer tox
Abeta42 oligos bind specific neuronal receptors, incl LilrB2
- leukocyte immunoglobulin-like receptor B2 : in immune system, neurons on growth cones/synapses
- activation of signaling by Abeta oligos → actin cytoskeletal disruption/synaptic loss
- evidence: transgenic AD mice (APP/PS1) who lack the mouse version of LilrB2 (PirB) → PROTECTED AGAINST NEURO DAMAGE/MEM DEFICIT!
SUMMARY
steps leading to AD
- overproduction of Abeta42 oligomers
- failure to clear toxic Abeta42 oligomers
neurofibrillary tangles
neurofibrillary tangles contain intracellular deposits of hyperphosphorylated tau (microtubule-associated) protein
- tau is normally phosphorylated as part of regulation, but hyperphos makes it insoluble/aggregation-susceptible
how do this affect cellular fx?
- microtubules play key role in cell/axon integrity and transport
- when tau is hyperphos → prone to aggregation → impairs axonal transport of cargo
tau is more typically associated with frontotemporal dementia
- NO GENETIC LINK to AD
so what is the link to AD?
formation of tau neurofib tangles appears to lie “downstream” of Abeta formation in neurodegen calcade
true connection is unclear
potential factors inducing hyper-phos of tau:
- tau mutation
- oxidative stress
- Abeta induced immune response (incr cytokine production)
amyloid cascade
diagnosis of AD
history
mental status
imaging and protein tests
- imaging: check brain volume changes/entorhinal cortex thickness
- UPSIT smell test
- PET scan (help differentiate AD from other forms of dementia)
- PET amyloid imaging (use PIB tracer that binds to Abeta42)
- serum levels of Abeta42 and tau
- low Abeta42→ more likely to develop AD (protein bound up in plaques and not cleared from brain)
- high tau → more likely to develop AD (pdt of neuronal degen?)
stages of AD
Stages I-II: entorhinal and hippocampal cortex
-
entorhinal cortex: main input into hippocampus, responsible for pre-processing input signals
- early sx: impaired sense of direction/object recog!
Stages III-IV: adjoining high order association areas of basal temporal neocortex
Stages V-VI: additional neocortical association areas, eventually extending in to primary areas of neocortex
- language/cognition profoundly affected
- psych sx present (major depression, delusions)
definitive diagnosis of AD requires post-mortem pathology
diff dx of AD
head trauma
HIV/AIDS
Huntington’s/Parkinson’s/Pick’s
vascular dementia (2nd most common)
Wernicke-Korsakoff (vitB1 deficiency, alcoholism, malnutrition)
tx for AD
- AchE inhibitors → incr amt of ACh in brain
- NMDA antagonist (Namenda) → protect brain from glu excitotoxicity
- both provide only temp symptomatic relief
- do not address underlying pathological process or progression
tx strategies for AD
- decrease beta- or gamma-secretase activity
- bind extracellular Abeta42 monomers to prevent aggregation (small molecules or ab immunotx)
- recent studies not promising and bad side effects; might be that it’s too late a step OR tx doesnt prevent oligo formation
- block cytokines (anti-infl crugs - COX1 inhibitors)
- antioxidants or free-radical scavengers to affect rate of cell death/andor offset neg conseqs (vitE)
exercise and AD
study: women 65+ for 8yr period
* more exercise? less likely to experience decline in metal fx than inactive
study: mouse model of AD
* physically active mice 50-80% lower plaque deposition
physical exercise (HR elevation for at least 30min sev times a week) is currently most effective tx we have to prevent/offset AD
mental exercise and AD
most susceptible to AD:
- projection neurons with long UN- or sparsely-myelinated axons
- specific nt systems (cholinergic systems of basal forebrain)
most severely affected areas involved in processing “default” activities (inward-directed mental activity; ex. introspection, daydreaming)
studies: education (directs brain activity away from default-mode and into task-specific modes) may delay onset of AD
