Pharmacological approaches for AD Flashcards

1
Q

What are neuritic/amyloid plaques ?

A
  • 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)
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2
Q

What is APP

A

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

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3
Q

What are neurofibrillary tangles?

A

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

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4
Q

What is tau

A
  • 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

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5
Q

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

A

Autosomal dominant fashion

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6
Q

How are the familial AD forms characterised?

A

-they are early onset

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7
Q

Outline the genes involved in familial cases of AD

A
  • 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
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8
Q

What form of dementia can mutations in tau cause?

A

-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
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9
Q

Outline how AD pathology and genetics are complementary

A

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
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10
Q

Which drugs are approved for treatment of AD in the UK

A
  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
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11
Q

finish writing revison cards for this

A

finish writing revision cards for this

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