Alzheimer's Disease Flashcards
What does dementia consist of?
Decline in memory, concentration, judgement
What are the 4 main pathologies of AD?
Brain atrophy - neuronal death
Extracellular AB plaques
Intracellular neurofibrillary tau tangles
Neuroinflammation
Name the 2 amyloid precursor protein cleavage pathways
Amyloidogenic
Non-amyloidogenic
What is the product of the non-amyloidogenic APP pathway and which enzymes are involved?
P3
Alpha- then gamma-secretase
What is the product of the amyloidogenic APP pathway and which enzymes are involved?
AB - multiple different length peptides - different aggregation likelihoods
Beta- then gamma-secretase
Which AB peptide is most likely to aggregate?
AB42
What is the name of the staging method for AB pathology?
Thal phases
Name the Thal phases and which brain areas they involve
1 - neocortex
2 - subcortical
3 - basal ganglia
4+5 - brainstem and cerebellum
Does AB level or distribution correlate with AD symptom severity?
No
What is the physiological role of tau?
Binds microtubules - stabilises
What is the effect of tau phosphorylation?
Favours dissociation from microtubules
How is tau altered in AD?
Hyperphoshorylated
Aggregates - forms paired helical neurofibrillary tangles
Does tau level or distribution correlate with AD symptom severity?
Yes
Name the Braak phases and which brain areas they involve
I-II - medial temporal lobe
III-IV - limbic system
V-VI - neocortex
What is the name of the staging method for tau pathology?
Braak stages
At which Braak stages are symptoms seen?
III-IV - early symptoms
V-VI - severe symptoms
How do activated microglia respond to AB plaques?
Surround
What does the amyloid cascade hypothesis suggest?
AB drives disease
Name the genes that cause familial AD
APP
PSEN1
PSEN2
What are the roles of PSEN1 and PSEN2 and how do their mutations affect this?
Form part of gamma-secretase
Mutations favour amyloidogenic pathway
Which gene encodes tau?
MAPT
What are the effects of crossing an APP mutant mouse with a tau KO mouse and what does this show?
No neuronal death, no cognitive impairment, no pathology
Tau necessary for degeneration - mediates mutant APP effect
What is the effect of inhibiting tau phosphorylation in AD animal models?
Prevents tangle formation
Improves cognitive deficits
Name genes linked to sporadic AD
ApoE
TREM2
What is the physiological role of ApoE?
Transports cholesterol to neurons
Name the 3 ApoE alleles, their relative frequencies, and their effects on sporadic AD risk
E2 - very rare - protective
E3 - common - neutral
E4 - fairly rare - increased risk
What is the physiological role of TREM2?
Affects microglia activation
How is TREM2 activity affected by AD-linked alleles?
Reduced microglial ability to phagocytose AB
Impaired microglia maturation
What are the 3 main genes types commonly linked to increased sporadic AD risk?
Immunity
Lipid
Endocytosis
How can AD iPSC-derived neurons be formed?
Take fibroblasts from AD patient
Add Yamanaka factors - become iPSCs
Add neuralising factors - become patient-derived neurons
Test in dish
How is in vitro corticogenesis performed using PSCs?
Dual SMAD inhibition and retinoids
Switches off stem cell property pathways - switches on neuronal development pathways
What is a weakness of in vitro corticogenesis?
Structure formed not layered
What are the strengths of patient-derived neurons?
Limitless supply in vitro
From patients with genetic mutation of interest
What are the weaknesses of patient-derived neurons?
Reductionist - only neurons - no glia and incorrect cortical layer order
Young immature neurons - modelling adult disease in ‘foetal’ neurons
