AD - Amyloid

Question 1

What is the function of APP?

Answer 1

Unknown

Thought to be involved in cell adhesion, neurite growth and synaptogenesis though

Question 2

What are the major and minor pathways APP processing?

Answer 2

Major - cleaved into harmless fragments

Minor - cleaved into amyloid beta

Question 3

What cleaves APP and where?

Answer 3

Alpha secretase between point 16 and 17

Question 4

What is the known protective variant of APP?

Answer 4

A673T

Question 5

What is the known pathological mutation of APP?

Answer 5

A673V

Question 6

Where is the APP gene found?

Answer 6

Chromosome 21

Question 7

Which other condition is AD strongly associated with?

Answer 7

Down Syndrome

Question 8

What is amyloid beta

Answer 8

A product of the cleavage of APP

39-42 peptides long

Question 9

What is the relationship between length of Ab and rate of disease?

Answer 9

Longer length = faster rate (generally)

Question 10

How do amyloid plaques form?

Answer 10

Monomers > oligomers > fibrils > diffuse plaques > amyloid plaques

Question 11

Which variant of Ab is most commonly found in plaques?

Answer 11

Ab42

Question 12

Which two variants of Ab form strong bonds between ionised side chains to form plaques?

Answer 12

42 and 43

Question 13

What occurs first: neurodegeneration or plaques?

Answer 13

Mouse models show neurodegen before plaque formation

Question 14

Does Ab induce apoptosis?

Answer 14

Well yes in cultered cells and post mortem brain tissue

But not in transgenic mice

Question 15

Does Ab cause oxidative damage?

Answer 15

Yes through the increase of ROS production

Question 16

What has been shown to be protective against Ab-induced-oxidative damage?

Answer 16

Antioxidant E and oestrogen

Question 17

What is Ab thought to do, but we are unsure?

Answer 17

Promote aggregation of Tau to form tangles

Insert into cellular membranes to disrupt integrity

Question 18

Why do we think that Ab plays a role in AD?

Answer 18

People diagnosed with AD have many more plaques in the brain than those without

Genetic mutations seen in AD also seem to cause increase Ab

Transgenic mice expression mutant human APP develop plaques and neurodegen

Aggregates Ab toxic to cells in culture and rhesus monkey brain. This would produce the clinical features of AD

Question 19

Outline the amyloid hypothesis.

Answer 19

APP broken down by a series of secretases
During this an insoluble Ab-42 accumulates and is deposited extracellularly
“Sticks” to this and other protein fragments like ApoE4 to form plaques

Question 20

Which genes are responsible for gamma secretases?

Answer 20

PSEN1 PSEN2

Question 21

Why are PSEN genes relevant to AD?

Answer 21

They are responsible for gamma secretases which cleave to form Ab