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NEUR0010 > Alzheimer's Disease > Flashcards

Alzheimer's Disease Flashcards

1
Q

What does dementia consist of?

A

Decline in memory, concentration, judgement

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2
Q

What are the 4 main pathologies of AD?

A

Brain atrophy - neuronal death
Extracellular AB plaques
Intracellular neurofibrillary tau tangles
Neuroinflammation

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3
Q

Name the 2 amyloid precursor protein cleavage pathways

A

Amyloidogenic

Non-amyloidogenic

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4
Q

What is the product of the non-amyloidogenic APP pathway and which enzymes are involved?

A

P3

Alpha- then gamma-secretase

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5
Q

What is the product of the amyloidogenic APP pathway and which enzymes are involved?

A

AB - multiple different length peptides - different aggregation likelihoods
Beta- then gamma-secretase

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6
Q

Which AB peptide is most likely to aggregate?

A

AB42

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7
Q

What is the name of the staging method for AB pathology?

A

Thal phases

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8
Q

Name the Thal phases and which brain areas they involve

A

1 - neocortex
2 - subcortical
3 - basal ganglia
4+5 - brainstem and cerebellum

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9
Q

Does AB level or distribution correlate with AD symptom severity?

A

No

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10
Q

What is the physiological role of tau?

A

Binds microtubules - stabilises

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11
Q

What is the effect of tau phosphorylation?

A

Favours dissociation from microtubules

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12
Q

How is tau altered in AD?

A

Hyperphoshorylated

Aggregates - forms paired helical neurofibrillary tangles

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13
Q

Does tau level or distribution correlate with AD symptom severity?

A

Yes

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14
Q

Name the Braak phases and which brain areas they involve

A

I-II - medial temporal lobe
III-IV - limbic system
V-VI - neocortex

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15
Q

What is the name of the staging method for tau pathology?

A

Braak stages

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16
Q

At which Braak stages are symptoms seen?

A

III-IV - early symptoms

V-VI - severe symptoms

17
Q

How do activated microglia respond to AB plaques?

A

Surround

18
Q

What does the amyloid cascade hypothesis suggest?

A

AB drives disease

19
Q

Name the genes that cause familial AD

A

APP
PSEN1
PSEN2

20
Q

What are the roles of PSEN1 and PSEN2 and how do their mutations affect this?

A

Form part of gamma-secretase

Mutations favour amyloidogenic pathway

21
Q

Which gene encodes tau?

A

MAPT

22
Q

What are the effects of crossing an APP mutant mouse with a tau KO mouse and what does this show?

A

No neuronal death, no cognitive impairment, no pathology

Tau necessary for degeneration - mediates mutant APP effect

23
Q

What is the effect of inhibiting tau phosphorylation in AD animal models?

A

Prevents tangle formation

Improves cognitive deficits

24
Q

Name genes linked to sporadic AD

A

ApoE

TREM2

25
Q

What is the physiological role of ApoE?

A

Transports cholesterol to neurons

26
Q

Name the 3 ApoE alleles, their relative frequencies, and their effects on sporadic AD risk

A

E2 - very rare - protective
E3 - common - neutral
E4 - fairly rare - increased risk

27
Q

What is the physiological role of TREM2?

A

Affects microglia activation

28
Q

How is TREM2 activity affected by AD-linked alleles?

A

Reduced microglial ability to phagocytose AB

Impaired microglia maturation

29
Q

What are the 3 main genes types commonly linked to increased sporadic AD risk?

A

Immunity
Lipid
Endocytosis

30
Q

How can AD iPSC-derived neurons be formed?

A

Take fibroblasts from AD patient
Add Yamanaka factors - become iPSCs
Add neuralising factors - become patient-derived neurons
Test in dish

31
Q

How is in vitro corticogenesis performed using PSCs?

A

Dual SMAD inhibition and retinoids

Switches off stem cell property pathways - switches on neuronal development pathways

32
Q

What is a weakness of in vitro corticogenesis?

A

Structure formed not layered

33
Q

What are the strengths of patient-derived neurons?

A

Limitless supply in vitro

From patients with genetic mutation of interest

34
Q

What are the weaknesses of patient-derived neurons?

A

Reductionist - only neurons - no glia and incorrect cortical layer order
Young immature neurons - modelling adult disease in ‘foetal’ neurons

NEUR0010 (9 decks)

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