Alzheimer's

Question 1

What differences are there in Alzheimer’s brains vs normal brains?

Answer 1

• Smaller overall
• Gyri have less grey matter
• Sulci are wider
• Hippocampus shrinks

Question 2

What are the two types of AD?

Answer 2

• Familial - if you have the genetic mutation, you get the disease (amyloid precursor protein Chr21)
• Sporadic - much more common. Not deterministic. Alleles increase your risk (ApoE Chr19 - E2 reduces risk, E4 increases risk)

Question 3

Why do you need to treat AD patients early?

Answer 3

• Once the brain has tangles, plaques and has shrunk, there is no fixing it
• Need to get it early to slow or stop the progression

Question 4

What is amyloidopathy?

Answer 4

• Plaques formed by extracellular deposits of amyloid-beta fibrils
• Aggregated peptides cleaved from the amyloid precursor protein
• Happens to all of us, but we can get rid of it in the CSF and venous system
• beta-sheets structure

Question 5

How is Amyloid precursor protein cleaved?

Answer 5

• Cleaved by secretase enzymes (alpha, beta and gamma)
• Normally cleaved by alpha then gamma, to make a soluble amyloid fragment and a soluble secondary fragment
• If it is cleaved by beta then gamma, insoluble plaques are formed.

Question 6

What is Presenilin?

Answer 6

• Makes the gamma secretase functional
• Mutations in the gene is what causes the excessive build up of amyloid beta
• presenilin 1 (Chr14), presenilin 2 (Chr1) associated with causing early onset familial alz

Question 7

What are PiB scans?

Answer 7

• Can use Pitsburgh B in PET scans
• Binds tightly to amyloid beta and can detect this in a PET scan
• AD patient will show lots of PiB activity, whereas a normal brain will show minimal
• Can use it to identify the cause of AD (i.e. AB rather than vascular or lewy bodies)

Question 8

What is Tauopathy?

Answer 8

• TAU is a scaffolding for nerve axons - hold them in place together
• In AD it gets excessively phosphorylated, tangles up and loses its filamentous structure, clogging up the axon
• Tend to emerge first in the hippocampus and temporal lobe, then as it gets more advanced, the parietal, frontal and then occipital - diffusing wave of morphology

Question 9

What do TAU tangles look like in EM vs normal?

Answer 9

• Normally there are “railway tracks” that carry important stuff along the axons
• in the tangled areas, the railway tracks dont work, and so nutrients, RNA, and metabolites wont get to the nerve ending - stop working

Question 10

What causes TAU hyper-polarisation?

Answer 10

Kinase enzymes such as PKA, CDK5 and GSK

Question 11

AB vs Tau: Cause or effect?

Answer 11

• Study found that Tau is required for the pathological effect of AB
• If there is no TAU present, then the AB will not produce degenerative plaques

Question 12

Name 4 drugs that can be used for AD

Answer 12

Cholinesterase inhibitors (Donepezil, Rivastigmine, Galantamine)
- NMDA receptor antagonist (Memantine)

Question 13

What was the Elan vaccine trial?

Answer 13

• AB deposits have been targeted

- Make antibodies which bind to the deposits in the brain and disperse the plaques