Neuro - AD

Question 1

What are the symptoms of AD?

Answer 1

Forget events, names, places etc
Confused
Personality changes
Mood swings
Disorientations
Loud and aggressive behavior

Question 2

Which part of the brain is first effected? and then where does it spread too?

Answer 2

Hippocampus which is involved in memory. Spreads too frontal lobes and back of the brain and then all through the cortex.

Question 3

What are the 2 neuropathological hallmarks of AD?

Answer 3

Plaques and tangles

Question 4

What is the theory of the amyloid cascade?

Answer 4

Cause e.g. gene –> Abeta peptide accumulation –> neurol injury –> Altered Tau metabolism –> Neuronal dysfunction and death –> dementia

Question 5

What is the main component of AD plaques?

Answer 5

A-beta peptide

Question 6

How is A-beta produced?

Answer 6

2 ways APP can be cleaved - non-amyloidogenic and amyloidogenic

Non-amyloidogenic - APP sits in the membrane and is cleaved by alpha-secretase (ADAM10) which makes CTFalpha and SAPPalpha. CTFalpha is further cleaved in the membrane by gamma-secretase into P3 and AICD.

Amyloidogenic - a trigger in the cell causes the switch to this route. APP is cleaved by beta-secretase (BACE10) into CTFbeta and SAPPbeta. CTFbeta is further cleaved by gamma-secretase which produces A-beta and AICD.

Question 7

Are there one or multiple alpha-secretases?

Answer 7

Multiple - ADAM 9/10/17

Question 8

Does ADAM10 cleave APP only?

Answer 8

No there are other proteins ADAM10 cleave and hence why upregulating it as a treatment can be problematic

Question 9

Where does beta-secretase cleave?

Answer 9

Met-Asp bond at N-terminal end of A-beta

Aspartate protease

Question 10

Does BACE1 only cleave APP?

Answer 10

No cleaves multiple proteins

Question 11

Is the gamma-secretase a single enzyme?

Answer 11

No it is a large complex where the proteins need to be bound together in a certain ratio to allow cleavage

Question 12

How many different gamma-secretase complexes exist? and where do they differ?

Answer 12

At least 4 different ones - changes in PS1/2 and Aph1a/1b

They have enhanced ability to cleave APP or other proteins

Question 13

Are the majority of AD cases sporadic or familial

Answer 13

90% are sporadic and occur after 65 years of age (late-onset)
10% are familial with mutations in Presenilin 1 and 2 and APP (early-onset) before 65 years old

Question 14

What happens with mutations in APP?

Answer 14

A-beta is not cut at a simple peptide and gamma-secretase cuts it at a number of different sites which depends on how the complex is assembled and how the C-terminal of APP fits into it
Cleavage to give A-beta 40 is safer than A-beta 42

Question 15

What does the flemish mutation cause?

Answer 15

Changes the structure of A-beta and enhances aggregation by modifying how it folds

Question 16

What does the Swedish mutation cause?

Answer 16

Increase b-secretase cleavage

Question 17

What does the Florida and Australian mutants cause?

Answer 17

Increase A-beta 42 which aggregates more rapidly

Question 18

Which form of A-beta aggregates quicker?

Answer 18

A-beta 42 aggregates quicker than A-beta 40

Question 19

Are there any protective mutations of APP?

Answer 19

Yes - A673T variant is more common in people 85+ who do not have AD
Very rare mutations
Causes a 20% reduction in lifelong production of A-beta
Provides proof of principle that reducing BACE-1 cleavage of APP may protect against AD
Also protects against cognitive decline

Question 20

What do the mutations in presenilins cause to happen?

Answer 20

In general cause APP to be moving up and down inside where the cleavage complex is occurring so get A-beta 40 vs 42 production

Question 21

What are the toxic species in AD?

Answer 21

Problem is that we all produce senile plaques however no correlation between A-beta senile plaques and AD. Started to identify smaller, soluble forms of A-beta which are rings or multimers and as they are soluble they can move around and be associated with membranes particularly the synapse interfering with communications between neurons and bind to neurons causing membrane impairment and toxic cell death

Question 22

What are the risk factor genes in sporadic AD? and how were these found?

Answer 22

APOE, CLU, PICALM and CRI

Found by meta-analysis of 74,000 people

Question 23

What are ApoE and CLU involved in?

Answer 23

A-beta clearance

Question 24

Are there any drugs to cure AD?

Answer 24

No only to temporarily relieve the symptoms so the disease is still progressing

Question 25

What are the 3 major areas for therapeutic intervention in AD?

Answer 25

1) . A-beta production - Inhibition of gamma or beta secretase, activation of alpha-secretase and altering APP trafficking
2) . A-beta degradation - activation of A-beta degrading enzymes or immunotherapy
3) . A-beta aggregate formation - preventing the toxic effects and making degradation easier