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M2 Neuron Brain Behavior > 9/28 Alzheimer's Disease - Matise > Flashcards

9/28 Alzheimer's Disease - Matise Flashcards

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1
Q

dementia

A

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
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2
Q

four major neurodegen dementias

A
  1. Alzheimer’s disease
  2. frontotemporal demential (formerly: Pick’s disease)
  3. dementia with Lewy bodies
  4. Creutzfeld-Jakob
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3
Q

common features of dementia syndromes

A
  • 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
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4
Q

sporadic forms of disease: risk factors

A

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

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5
Q

neuropathology of Alzheimer’s Disease

A
  1. presence of neuritic plaques and tangles
  2. synaptic and neuronal loss due to apoptosis
    • ​reduced brain volume due to atrophy
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6
Q

clinical features of AD

A

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

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7
Q

AD and age

A

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
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8
Q

neuritic plaques

A

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

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9
Q

amyloid beta-protein

  • how does it form?
  • how does the brain attempt to clear it out?
A

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
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10
Q

“amyloid hypothesis”

A

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
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11
Q

evidence for amyloid hypothesis

mouse models

A

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
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12
Q

genetic evidence for amyloid hypothesis

A
  1. 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
  2. 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
  1. mutations that reduce production/deposition of Abeta42 associated with protective effect against AD!
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13
Q

role of apoE

A

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
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14
Q

role of Presenilin

A

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

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15
Q

other genes linked to sporadic AD

  • clusterin/apolipoproteinJ
  • CR1
  • PICALM
A

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
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16
Q

graphical summary of production of Abeta42 and involved genetic factors

A
17
Q

amyloid hypothesis:

plaques vs oligomers

conflicting evidence

A

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
18
Q

Abeta42 oligomer toxicity

why might oligos be worse than plaques??

A

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)
19
Q

LilrB2 and oligomer tox

A

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!
20
Q

SUMMARY

steps leading to AD

A
  1. overproduction of Abeta42 oligomers
  2. failure to clear toxic Abeta42 oligomers
21
Q

neurofibrillary tangles

A

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
22
Q

tau is more typically associated with frontotemporal dementia

  • NO GENETIC LINK to AD

so what is the link to AD?

A

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:

  1. tau mutation
  2. oxidative stress
  3. Abeta induced immune response (incr cytokine production)
23
Q

amyloid cascade

A
24
Q

diagnosis of AD

A

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?)
25
Q

stages of AD

A

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

26
Q

diff dx of AD

A

head trauma

HIV/AIDS

Huntington’s/Parkinson’s/Pick’s

vascular dementia (2nd most common)

Wernicke-Korsakoff (vitB1 deficiency, alcoholism, malnutrition)

27
Q

tx for AD

A
  1. AchE inhibitors → incr amt of ACh in brain
  2. NMDA antagonist (Namenda) → protect brain from glu excitotoxicity
  • both provide only temp symptomatic relief
  • do not address underlying pathological process or progression
28
Q

tx strategies for AD

A
  1. decrease beta- or gamma-secretase activity
  2. 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
  3. block cytokines (anti-infl crugs - COX1 inhibitors)
  4. antioxidants or free-radical scavengers to affect rate of cell death/andor offset neg conseqs (vitE)
29
Q

exercise and AD

A

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

30
Q

mental exercise and AD

A

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

M2 Neuron Brain Behavior (53 decks)

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