Molecular Biology of Alzheimer's Flashcards
(33 cards)
what is the amyloid cascade hypothesis
APP (amyloid precursor protein) and amyloid beta cause AD
what two things can amyloid beta peptide turn into?
aggregate into senile plaques
neurotoxic ADDL oligomers
what is the primary pathology of AD
senile plaques
neurofibillary tangles
what are the secondary changes of AD pathology
neuronal loss
synaptic degradation
glial activation (inflammation)
vascular pathology (blood vessels)
outline senile plaques
made of amyloid beta 40-42aa peptide
extracellular protein aggregate
cause synaptic disruption
why are downs syndrome and AD linked?
amyloid peptide comes from larger amyloid precursor protein (APP) which is found on chromosome 21
as people with downs syndrome have 3 copies of chromosome 21, they have greater chance of developing AD as more APP
outline amyloid precursor protein
found in all cells as type I transmembrane protein with the N terminus sticking out the cell and C terminus in the cell
only function known is that protease nexin II is involved in the regulation of blood clotting
what happens if a transgenic mouse is injected with APP?
develops amyloid deposits and tau pathology
shows memory deficits
how is the APP protein cleaved
by two secretase enzymes
beta secretase
gamma secretase
this creates amyloid
which then forms amyloid beta plaques and ADDLs
does generation of amyloid beta occur in non AD people?
yes - but this amyloid is created by cleaving APP with alpha secretase enzyme and not beta or gamma
majority is produced in this way
what are the two alpha secretase enzymes which cleave APP in the ‘good pathway’
ADAM10 and TACE
how can we increase decrease the likelihood of beta secretase forming amyloid beta?
increase amount of alpha secretase enzymes
e.g Talsaclidine - acts on muscarinic M1 receptor to increase alpha but doesnt know improvement in cognition
what is alpha secretase activity dependant on and what study showed this?
cholesterol
rabbits treated with high fat diet developed senile plaques
how do beta and gamma secretase cut APP
beta secretase cuts first,
followed by gamma secretase
amyloid beta then stacks to make senile plaque - this could take a while which could explain age-related onset - or maybe not cleared very well at old ages
how much of AD is familial
10%
what do genetic mutations in familial AD do to the enzymes?
mutations in APP around beta-amyloid sequence make APP a better substrate for beta and gamma secretase enzymes
what does ADDL stand for
amyloid-beta derived diffusible ligands
outline ADDLs
toxic component of senile plaques
stage between amyloid beta and plaque formation
single amyloid beta monomer stacks to make oligomer before making plaque
interact with nerve cells and cause abnormal transmission/kill cells
why do researchers think ADDLs are the actual toxic component of AD as opposed to senile plaques
transgenic mice which produce excessive amounts of amyloid beta, show memory impairment before senile plaques appear in the brain
what did Schenk et al 1999 find in AD mice
immunisation of mice with amyloid beta peptide lead to them having reduced deposition of senile plaques in the brain
how did immunisation work in humans?
autopsy of patients showed reduced amyloid beta deposits but trial was stopped as patients developed aseptic meningitis
now passive immunisation is being engineered from humanised monoclonal antibodies - some success in clearing amyloid deposits but modest e.g Lecanemab, Aducanumab
what are the two gene mutations associated with AD and what do they do
presenilin - PSEN1 and PSEN2
make gamma secretase more active (cluster around membrane domain) to increase amyloid beta production this way
how does presenilin exist?
large complex with other proteins
located in endoplasmic reticulum and trans golgi network
cell surface location
what does the gamma secretase presenilin complex do
mutations of PSEN1/2 increase gamma secretase activity, form an intramembrane pore
cleave broad range of signalling molecules - possibility this causes neurones to undergo programmed cell death
