Pharmacological approaches for AD Flashcards
What are neuritic/amyloid plaques ?
- 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)
What is APP
-Amyloid precursor protein is a type 1 membrane spanning protein that is processed by secretase proteases to produce Abeta
What are neurofibrillary tangles?
Intra-neuronal pathologies and in the electron microscope comprise aggregates of paired helical filaments (PHF)
-The principle biochemical constituent of PHF is TAU
What is tau
- 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
some forms of AD are familial and passed down through families. What mode of inheritance are they passed down in?
Autosomal dominant fashion
How are the familial AD forms characterised?
-they are early onset
Outline the genes involved in familial cases of AD
- 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
What form of dementia can mutations in tau cause?
-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
Outline how AD pathology and genetics are complementary
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
Which drugs are approved for treatment of AD in the UK
- ) acetylcholinesterase inhibitors:
- Ach levels are reduced and cholinergic neurons lost in AD - )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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