Alzheimer's Disease

Question 1

Why is Amyloid Beta-42 (AB42) linked to AD?

Answer 1

Common MOA in AD age 65+, early onset, and familial.

Question 2

Where does AB42 come from?

Answer 2

Amyloid precursor protein (APP), a protein that is ubiquitously produced in mammalian cells, that was extracellularly cleaved by beta-secretase, followed by transmembrane cleavage by gamma-secretase.

Question 3

What is the normal processing of beta-amyloid precursor protein?

Answer 3

Favored pathway is alpha secretase followed by gamma secretase.

Question 4

Cleavage of beta-APP by beta-secretase followed by gamma-secretase yields what two proteins?

Answer 4

AB40 and AB42, which are toxic in vitro.

Question 5

APP is coded on which chromosome?

Answer 5

Chromosome 21

Question 6

What protein has a key role in amyloid processing and clearance?

Answer 6

Apolipoprotein E

Question 7

Which apolipoprotein E specifically increases amyloid depositon and increase in AD?

Answer 7

Apo e4

Question 8

There is a mutation near the B-cleavage site. What happens to Amyloid beta protein production?

Answer 8

Decrease, thus a decrease in onset of AD.

Question 9

A mutation in presenilin 1 or 2 can cause increased production of what protein?

Answer 9

AB42.

Question 10

What is the difference between dominant inherited AD and non-dominated inherited AD?

Answer 10

Dominant: missense mutation on APP, presenilin 1 or 2, which causes increases in AB42 throughout life.
Non-dom: faliure of Amyloid-beta protein clearance (Apo E e4 produced, and not the others ones that actually clears it)

Question 11

What are some potential interventions to prevent/ delay AD?

Answer 11

1) decrease AB42 production by modulating secretase activity.
2) increase AB42 clearance
3) decrease AB42 toxicity
4) decrease damage to synapses/ neurons
5) compensate for neuronal dysfunction