AD mouse models

Question 1

What were the early pathways identified in GWAS?

Answer 1

Immune response
Cholesterol metabolism
Endocytosis/ synaptic function

Question 2

Familial AD features

Answer 2

EOAD
3% of cases but severe
Mutations in APP, PSEN1,PSEN2
Increase toxic ratio Ab 1-42

Question 3

What is TREM2 and role in AD?

Answer 3

Anti-inflammatory response
Receptor on surface of microglia -involved in immune response in AD and other NDDs.

Also Hong lecture

Question 4

What is the TASTPM mouse model

Answer 4

The TASTPM mouse model is a double transgenic mouse model used to study Alzheimer’s disease (AD). It expresses two key human proteins involved in AD: the amyloid precursor protein (APP) with the Swedish mutation (hAPP695swe) and presenilin-1 (PSEN1) with the M146V mutation.

Question 5

How many mouse models of AD are there

Answer 5

160

Question 6

Which knockin mouse model show plaques

Answer 6

APP knockin (Swedish, Beyreuthian and Arctic)
-Increased glutamte
-Deposition of plaques causing synapse loss

Question 7

Disadvantages of previous transgenic mouse model?

Answer 7

-Mice do not naturally form AD & Tangles in one model.
-Need for high overexpression of mutation

Question 8

Which knockin mouse model show tangles?

Answer 8

Tau transgenic mice
Tau knockin mouse
Cognitive decline

Question 9

What should the ideal mouse model show?

Answer 9

Early AD- (Plauqes, subtle behavioural changes)

Late AD- (delayed tau tangles and cell death) and cognitive impairment

Question 10

Disadvantage of knockin mice

Answer 10

Phenotype not as strong

Question 11

Two main forms of APP knockin mice and do they form tangles

Answer 11

APP NF-L

APP NL-G-F

they do not form plaques-no ND either.

Question 12

Describe APP NF-L model

Answer 12

Plaques at 9 months
increase Ab 1-42

Question 13

Describe APP NL-G-F

Answer 13

Plaques at 2 months (earlier)
causes change to Ab to create oligomer

Question 14

What happens to PPR in Ab plaques presence

Answer 14

Reduced PPR so increased probability in glutamate release in first pulse.

Question 15

How many vesicles are normally released at CA3-CA1 synapse?

Answer 15

5-10 ready. More than 8 are rarely released in one go. This is also dependent on calcium levels for vesicle fusion and NT release
Under lower calcium conditions, they tend to release only 1 glutamate vesicle. High amount released in high calcium conditions.