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NMH: Module 2 > AD: Neuropathology > Flashcards

Flashcards in AD: Neuropathology Deck (28)
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Key neuropathological features in AD?

- extracellular Aβ plaques within brain parenchyma

- neurofibrillary tangles (NFTs)

- cerebral amyloid angiopathy (Aβ deposition in blood vessel)

- neuronal loss (cerebral atrophy)


Extracellular Aβ plaques ("senile"/"neuritic" plaques) forms?

Classical (neuritic) or diffuse


Dustbin hypothesis of extracellular Aβ plaques?

Cells expel Aβ (as too much intracellularly) -> accumulates in EC space -> glial reaction


NFTs correlation w/ dementia?

Best correlation w/ dementia (used to grade pathology)


NFTs composition and forms

Contains paired helical filaments

Found as NFT or neuropil threads (dendrites)


How to stain for NFTs?

Use antibody against hyperphosphorylated Tau or silver staining


Describe the cholinergic hypothesis

Increased age -> decreased ACh turnover

[AD is characterised by cerebral cholinergic denervation]


Cholinergic hypothesis relationship w/ cognition?

Cholinergic defects underlie memory loss and related cognitive problems

Decreased cholinergic markers correlate w/ dementia severity


Variants of treatment using cholinergic hypothesis (+ effectiveness)?

Lessathine : ineffective as precursor can't reach pre-synaptic terminal

Ligand: minimally effective

AChEi: main treatment]- mild benefits in early AD but doesn't prevent progression


Currently available AD treatments?

- Anticholinesterases: donepezil, tacrine, rivastigmine

- nACh receptors (increases stimulation): galantamine

- Glutamate antag: memantine]- may also be useful in vasc. dementia


Describe the amyloid cascade hypothesis

Any factor that alters AP metabolism to favour Aβ production could favour AD

Altered APP metab -> Aβ deposition -> neuritic Aβ plaques -> NFTs and neuronal damage -> dementia


Provide an overview of Braak's staging

[for Tau, which correlates w/ AD progression better than tau]

1. transenterohinal region, medial temporal lobe
2, extends to enterohinal region, posterior hippocampus
3. adjacent entorhinal cortex
4. rest of temporal cortex
5. occipital cortex (visual association areas)
6. occiptal cortex (primary visual cortex)


At what stages of Braak's staging, do cognitive symptoms appear?

Between 3 and 4


What is APP and its composition?

Membrane bound glycoprotein (carboxy intracellular, NH2 extracellular, beta-amyloid in membrane region)


Where is APP found in the body?

In all cells


What is non-amyloidogenic cleavage?

alpha-secretase cuts within Aβ sequence]- main physiological pathway, non-pathological


What is amyloidogenic cleavage?

beta-secretase and gamme-secretase to release intact Aβ]- pathological protein


Outcome Aβ accumulation intracellularly?

Intracellular Aβ -> Ca2+ dysfunction -> mitoch. and proteasome inhibition -> ROS

[extracellular plaque is a "dustbin"]


Risk factors for AD?

- age
- FHx
- Down's syndrome
- Previous head trauma
- PD
- depression


Describe the mutations in Familial AD?

APP mutation: codon 717 (point mutation val-> lle)]- london mutation

Presenilin 1/2: role in intracellular signalling]- accounts for most familial AD; presenilin has gamma-secretase


AD risk genes?

- ApoE4: role in lipid metab

- TREM2: heterozyhous variant

- GWAS SNPs: modify risk e.g. Apoe4


ApoE4 significance?

[role in lipid metabolism on Chr19]

50% of AD have E4 allele

E4 homozyogte -> 10x greater risk

Associated w/ late onset AD


Relationship between head injury and AD?

- acute head injury associated w/ AD-like changes "dementia pugilistica" aka CTE]- if survived, would they develop AD?

30% of head injury develop Aβ deposits withing weeks (these ppl have high ApoE4 incidence)


Mechanism relating head injury and AD?

Cytokine cycle:

Microglial activation -> normally resolves but +ve feedback -> neuroinflammation (IL-1,ApoE4) -> neurodegenerative


Post Mortem Examination Findings:
Overview of therapeutic approaches for AD?

- stop Aβ aggregation]- if plaques are dustbin, this causes increased intracell accumulation

- clear Aβ plaques

- reduce Aβ expression]- but APP is a normal physiological protein

- alter Aβ expression (enhance a-secretase, inhibit b/g-secretase)

- anti-inflammatories (assoc. between NSAID use and low AD risk)

- tissue transplants


Animal studies for clearing Aβ plaques?

Vaccination -> antibodies against Aβ -> clear brain pathology

Autopsy case report showed Aβ cleared but no change in disease course]- but 25% didnt have AD

human studies stopped due to meningioencephalitis


Significance of Chr21 in AD?

Variety of point mutations: London mut, Swedish mut, Arctic, HCHWA-D

All these mutations are at the secretase sites- sites that will increase beta-amyloid


Significance of presinilin in AD?

Part of the gamma-secretase complex