Neuro - AD Flashcards
What are the symptoms of AD?
Forget events, names, places etc Confused Personality changes Mood swings Disorientations Loud and aggressive behavior
Which part of the brain is first effected? and then where does it spread too?
Hippocampus which is involved in memory. Spreads too frontal lobes and back of the brain and then all through the cortex.
What are the 2 neuropathological hallmarks of AD?
Plaques and tangles
What is the theory of the amyloid cascade?
Cause e.g. gene –> Abeta peptide accumulation –> neurol injury –> Altered Tau metabolism –> Neuronal dysfunction and death –> dementia
What is the main component of AD plaques?
A-beta peptide
How is A-beta produced?
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.
Are there one or multiple alpha-secretases?
Multiple - ADAM 9/10/17
Does ADAM10 cleave APP only?
No there are other proteins ADAM10 cleave and hence why upregulating it as a treatment can be problematic
Where does beta-secretase cleave?
Met-Asp bond at N-terminal end of A-beta
Aspartate protease
Does BACE1 only cleave APP?
No cleaves multiple proteins
Is the gamma-secretase a single enzyme?
No it is a large complex where the proteins need to be bound together in a certain ratio to allow cleavage
How many different gamma-secretase complexes exist? and where do they differ?
At least 4 different ones - changes in PS1/2 and Aph1a/1b
They have enhanced ability to cleave APP or other proteins
Are the majority of AD cases sporadic or familial
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
What happens with mutations in APP?
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
What does the flemish mutation cause?
Changes the structure of A-beta and enhances aggregation by modifying how it folds
What does the Swedish mutation cause?
Increase b-secretase cleavage
What does the Florida and Australian mutants cause?
Increase A-beta 42 which aggregates more rapidly
Which form of A-beta aggregates quicker?
A-beta 42 aggregates quicker than A-beta 40
Are there any protective mutations of APP?
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
What do the mutations in presenilins cause to happen?
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
What are the toxic species in AD?
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
What are the risk factor genes in sporadic AD? and how were these found?
APOE, CLU, PICALM and CRI
Found by meta-analysis of 74,000 people
What are ApoE and CLU involved in?
A-beta clearance
Are there any drugs to cure AD?
No only to temporarily relieve the symptoms so the disease is still progressing
What are the 3 major areas for therapeutic intervention in AD?
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
