Pharmacological approaches for AD

Question 1

What are neuritic/amyloid plaques ?

Answer 1

• Neuritic plaques are areas of degenerating neurites that surround an ‘amyloid’ core
• The amyloid core is extracellular and its main protein constituent is Beta-amyloid(Abeta)
• Abeta is a short 40-43 AA peptide that is derived from a larger protein, the amyloid precursor protein(APP)

Question 2

What is APP

Answer 2

-Amyloid precursor protein is a type 1 membrane spanning protein that is processed by secretase proteases to produce Abeta

Question 3

What are neurofibrillary tangles?

Answer 3

Intra-neuronal pathologies and in the electron microscope comprise aggregates of paired helical filaments (PHF)
-The principle biochemical constituent of PHF is TAU

Question 4

What is tau

Answer 4

• A microtubule associated protein that functions to stabilize microtubules, particularly in axons
• Microtubules are essential for generating and maintaining axonal morphology. They also serve as ‘rails’ for kinesin and dynein motors that transport essential proteins/organelles to and from the neuronal cell body to the synapse
• Tau is a phosphoprotein and phosphorylation on some sites inhibits taus’ ability to bind tubulin and promote/stabilise microtubules

-Tau is abnormally hyperphosphorylated in AD- may lead to loss of microtubules and damage axonal morphology and transport

glycogen synthase kinase-3beta(GSK3beta) and cyclin dependent kinase-5/p35 are the favoured kinases for phosphorylating Tau in AD

Question 5

some forms of AD are familial and passed down through families. What mode of inheritance are they passed down in?

Answer 5

Autosomal dominant fashion

Question 6

How are the familial AD forms characterised?

Answer 6

-they are early onset

Question 7

Outline the genes involved in familial cases of AD

Answer 7

• APP
• Presenilin-1
• Presenilin-2
• duplication of APP gene causes familial AD
• Down’s syndrome pts develop typical AD pathology and this is caused by trisomy of chromosome 21; the APP gene resides on chromosome 21

Question 8

What form of dementia can mutations in tau cause?

Answer 8

-Fronto-temporal dementia with Parkinsonism linked to chromosome 17(FTDP-17)

• Most disease-causing mutations affect the tubulin binding domains and lower tau affinity for microtubules.
• Others affect splicing of the tau gene to increase the amount of tau that contains 4 rather than 3 microtubule binding domains

Question 9

Outline how AD pathology and genetics are complementary

Answer 9

1.) Pathology=amyloid plaques and Abeta
genetics=mutations in APP from which Abeta is derived and the key gamma-secretase component presenilin
2.)Pathology=neurofibrillary tangles and tau
Genetics=mutations in tau cause a related form of dementia(FTDP-17)

• AD pts with mutations in APP or presenilin develop amyloid plaques and neurofibrillary tangles
• FTDP-17 pts with Tau mutations develop only neurofibrillary tangles
• This suggests that APP and Abeta are UPSTREAM of tau in pathogenic process

Question 10

Which drugs are approved for treatment of AD in the UK

Answer 10

1. ) acetylcholinesterase inhibitors:
   - Ach levels are reduced and cholinergic neurons lost in AD
2. )NMDA receptor antagonists
   - NMDA(fast response)& AMPA(slow response) glutamate receptors are then activated which leads to elevated calcium levels and excitotoxicity
   - Memantine(Ebixa) an uncompetitive NMDA receptor antagonist is licenced for moderate-severe AD

Question 11

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Answer 11

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