Flashcards in AD: Neuropathology Deck (28)
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?
- Down's syndrome
- Previous head trauma
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
[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?
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