Alzheimer's Disease Flashcards
What are the two key features of AD pathology?
1) Amyloid plaques (extracellular)
2) Neurofibrillary tangles
- These cause neuronal cell death
What is the main constituent of amyloid plaques?
Beta-amyloid (Aβ(1-42)) - short peptide which can aggregate derived from amyloid precursor protein (APP), a type 1 membrane spanning protein
What enzymes process APP to produce Aβ?
(β and γ) Secretase proteases
Describe the three types of secretases
1) α secretase - cleaves APP within the Aβ sequence so doesn’t produce Aβ
2) β secretase (BACE1) - cleaves APP at N terminus of Aβ sequence so produces Aβ (with γ secretase)
3) γ secretase - cleaves APP at C terminus of Aβ sequence so produces Aβ with β secretase but doesn’t produce Aβ with α secretase, contains presenilin (PSEN-1 or 2)
What are the products of APP processing by α and γ secretase (normally dominant)?
sAPPα, p3 and C terminus stump
What are the products of APP processing by β and γ secretase?
sAPPβ, Aβ and C terminus stump
What is another substrate of γ secretase involved in development?
NOTCH
What are neurofibrillary tangles?
- Intraneuronal pathologies
- Aggregates of paired helical filaments (PHF)
What is the main constituent of PHF?
Tau
What is tau?
- A microtubule associated protein which stabilises microtubules through binding to tubulin esp. in axons
- It is regulated by phosphorylation and in adults is less phosphorylated so that it sticks tighter to microtubules and prevents them from being more dynamic
What happens to tau in AD?
- Tau is abnormally hyperphosphorylated in AD making it aggregate like Aβ
- This may lead to detachment of tau from microtubules, destabilisation of microtubules, loss o microtubules and damage to axonal morphology and transport
What are the two kinases that phosphorylate tay in AD?
GSK3β and NCDK-5/p35
What autosomal dominant mutations can cause early onset (40s-50s) familial AD?
Mutations in genes that code for APP (clustered around Aβ sequence, inhibit α secretase and enhance β secretase and Aβ42 production by γ secretase), PSEN-1 and PSEN-2 (increase Aβ species)
What is the link between Down’s syndrome and AD?
- Duplication of APP gene causes familial AD bc excess Aβ
- Down’s syndrome patients develop typical AD pathology (plaques and tangles) in their 40s bc APP gene resides on chromosome 21
What are the actions of the APP mutations?
- Increase total Aβ production e.g. by making APP a better substrate for BASE1/beta secretase
- Increase production of longer 1-42 rather than 1-40 Aβ species → Aβ1-42 is believed to be pathogenic
What do mutations in tau cause?
FTD with Parkinsonism linked to chromosome 17 (FTDP-17)
Which gene variants contribute the most to genetic risk for developing AD?
- APOE gene
- Two variants, one from each parents
- If E2/E2, probably won’t developing AD at all
- E4/E4 highest risk but not diagnostic or certain
What are the neuritic plaques?
- Plaques sitting next to neurons that are dying
- These are the ones most closely associated with symptoms
How can amyloid plaques and tau be monitored in vivo?
PET scan using radio tracer that has been tagged to a ligand that is v specific for amyloid or tau
What are the parts of progressive pathology in AD (shared by other neurodegenerative diseases)?
1) Synaptic dysfunction
2) Neuron loss - slow, causes symptoms
3) Reactive (micro)gliosis - in reaction to build up of plaques, tangles and neuronal loss other brain cells react
- Astrocytes (glia) and microglia become activated in response to those pathologies and change shape and cause damage by constantly emitting toxins and damaging neurons further, leading to neurodegeneration
Why does microglia and astrocyte activation occur?
Microglia react to the protein aggregates and dysfunctional dying neurons as if they are pathogens
What part of the brain is involved in end stage AD?
The whole brain, atrophy (starts in hippocampus)
Describe the progressive neuronal cell loss in AD
- Starts in entorhinal cortex which contains the hippocampus
- Then moves and spreads to the basal forebrain and eventually the whole brain as there is neuronal to neuronal transmission of hyperphosphorylated tau which then aggregate wherever they go (explains pattern of distribution of neurons and variation)
What imaging technique can be used to see brain atrophy?
MRI
