Alzheimer's Disease

Question 1

What does dementia consist of?

Answer 1

Decline in memory, concentration, judgement

Question 2

What are the 4 main pathologies of AD?

Answer 2

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

Question 3

Name the 2 amyloid precursor protein cleavage pathways

Answer 3

Amyloidogenic

Non-amyloidogenic

Question 4

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

Answer 4

P3

Alpha- then gamma-secretase

Question 5

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

Answer 5

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

Question 6

Which AB peptide is most likely to aggregate?

Answer 6

AB42

Question 7

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

Answer 7

Thal phases

Question 8

Name the Thal phases and which brain areas they involve

Answer 8

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

Question 9

Does AB level or distribution correlate with AD symptom severity?

Answer 9

No

Question 10

What is the physiological role of tau?

Answer 10

Binds microtubules - stabilises

Question 11

What is the effect of tau phosphorylation?

Answer 11

Favours dissociation from microtubules

Question 12

How is tau altered in AD?

Answer 12

Hyperphoshorylated

Aggregates - forms paired helical neurofibrillary tangles

Question 13

Does tau level or distribution correlate with AD symptom severity?

Answer 13

Yes

Question 14

Name the Braak phases and which brain areas they involve

Answer 14

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

Question 15

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

Answer 15

Braak stages

Question 16

At which Braak stages are symptoms seen?

Answer 16

III-IV - early symptoms

V-VI - severe symptoms

Question 17

How do activated microglia respond to AB plaques?

Answer 17

Surround

Question 18

What does the amyloid cascade hypothesis suggest?

Answer 18

AB drives disease

Question 19

Name the genes that cause familial AD

Answer 19

APP
PSEN1
PSEN2

Question 20

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

Answer 20

Form part of gamma-secretase

Mutations favour amyloidogenic pathway

Question 21

Which gene encodes tau?

Answer 21

MAPT

Question 22

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

Answer 22

No neuronal death, no cognitive impairment, no pathology

Tau necessary for degeneration - mediates mutant APP effect

Question 23

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

Answer 23

Prevents tangle formation

Improves cognitive deficits

Question 24

Name genes linked to sporadic AD

Answer 24

ApoE

TREM2

Question 25

What is the physiological role of ApoE?

Answer 25

Transports cholesterol to neurons

Question 26

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

Answer 26

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

Question 27

What is the physiological role of TREM2?

Answer 27

Affects microglia activation

Question 28

How is TREM2 activity affected by AD-linked alleles?

Answer 28

Reduced microglial ability to phagocytose AB | Impaired microglia maturation

Question 29

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

Answer 29

Immunity Lipid Endocytosis

Question 30

How can AD iPSC-derived neurons be formed?

Answer 30

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

Question 31

How is in vitro corticogenesis performed using PSCs?

Answer 31

Dual SMAD inhibition and retinoids | Switches off stem cell property pathways - switches on neuronal development pathways

Question 32

What is a weakness of in vitro corticogenesis?

Answer 32

Structure formed not layered

Question 33

What are the strengths of patient-derived neurons?

Answer 33

Limitless supply in vitro | From patients with genetic mutation of interest

Question 34

What are the weaknesses of patient-derived neurons?

Answer 34

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