Alzheimers Flashcards
Define alzheimers
irreversibly progressive neurodegenerative disease that starts in the temporal lobe and progresses to anterior and posterior lobes resulting in interference of daily functioning
What is the Pathophysiology of Alzheimers?
Plaques- beta-amyloid proteins which are extracellular and tangles - hyper-phosphorylated tau proteins which are intracellular
Both are insoluble
Talk about the APP protein
the APP protein when cleaved by beta and gamma secratases is called amyloid beta
the APP protein itself is a transmembrane protein and the gene encoding this is on chromosome 21
what are the genes implicated in BA plaques?
APP
PS1(most common)
PS2
APOE4
Talk about the APP protein and what the secratases do to it?
The APP protein is a transmembrane protein that is cleaved by secratases alpha, gamma, and beta
Mutations in the APP gene (chrosome 21) is concentrate around the cleavage site of the protein where gamma secratase acts
what does Johnson et al 2012 say?
Mutations in APP at the Beta site of the APP that results in 40% of reduced formation of the amyloidogenic peptide is protective against alzheimers
this mutation is alanine—threo673
What effects does presinillin have on the beta amyloid plaques?
causes incomplete digestion (loss of function) of the beta amyloid plaques , therefore increase in beta amyloid plaques
What is protective against the beta amyloid toxicity?
vitamin E and oestrogen are protective
Talk about the three secratases
Alpha -cleaves the APP PROTEIN and is non-amyloidogenic
Beta- APP cleaving enzyme that is amyloiogenic
Gamma- complex of presenilins 1/2 and is amyloidogenic
Talk about the transformation of beta amyloid from monomers to amyloid plaques
this is facilitated by zinc/copper
How does AB plaques cause alzheimers disease?
induces apoptosis in cells some of which may be inducing ROS production
insertion into cell membranes and disrupt integrity
may promote tau aggregation
What are neurofibrillary tangles?
sticky abnormal phosphorylation of tau that helps to stablize microtubules, is the tau toxic or the loss of function of the microtubules toxic? Thats the real question
well tau knockout is normal and its the presence of abnormal TAU causing neurofibrillary tangles rather than loss of function that is toxic
Discuss the phosphorylation of Tau
Tau usually gets phosphorylated but it is the ABNORMAL PHOSPHORYLATION OF TAU that messes things up , mutations in the proteins that regulate the phosphorylation of tau could contribute to neurofibrillary tangles
imbalance between kinases and phosphotases causes aggregation
What are the three different isoforms of ApOE protein?
Isoforms are E2, E3, E4
Produced in the liver an brain and synthesized by the glia in brain
It’s the bodies primary transport protein
APOE proteins bind beta amyloid and enhance accumulation of plaque
How does APOE proteins exert their actions?
the APOE portein cause more lipid rafts and results in more LIPID i.e. cholestrol which causes more B and Y secratases to act causing the increase generation of AB
Influences AB clearance
What mediates the influx of AB Peptides across the BBB to the brain?
RAGE
In alzheimers name some loss of function mutations
IDE- degrades soluble oligomers intracellularly
NEP- degrades extracellular plaques
How does APOE influence the clearance of AB?
AB clearance ecreases because AB may have lower affinity for APOE4 or oligomerization because AB may have increase affinity for APOE4
What is the multifactorial threshold model?
alleles have low penetrance
many risk alleles ADD UP
additive environmental factors- cause liability and when this reaches a threshold value the disease process starts
which gene is implicated in late onset alzheimers?
ApOE4
What is the amyloid cascade hypothesis?
imbalance between the production and clearance
production- increase in familial alzheimers
clearance - increase in sporadic parkinsons??
Name some acetylcholinestarse inhibitors and their mechanism of action
they prevent the breakdown of acetylcholine into choline and acetate so that there is more acetylcholine
galantamine, donepazil, rivastigmine
How does memantine work?
its a selective extrasynaptic NMDAR antagonist
How are future therapeutics aimed at targetting AB an preventing the formation?
targetting gamma secratase- but actually its important in other stuff
Beta secratase- knockout is fine therefore lesser effects if we target this instead?
Alpha secratase- stimulating its activity could decrease AB cause it cleaves peptides instead of Y or B - bryostatin which is a protein kinase C Inhibitor enhances the actions of alpha secretase
How are future therapeutics aimed at preventing aggregation?
clioquinol is a zinc copper chelator prevents the aggregation of beta amyloid because beta sheet prouction is facilitated by glycosaminoglycans therefore blocking this could be a target
Regland 2001
How are future therapeutics targetting the clearance of AB?
injections of AN-1792 causes antibody against alzheimers but this was abandonned - THIS DID NOT WORK
how about the antibody aducanumab? its meant to reduce AB plaques in alzheimers disease
USS to physically disrupt the plaques
Talk about Tau hypothesis
hyperphosphorylated TAU causes paired helical fragments which then causes neurofibrillary tangle production
impaired axonal transport because it cannot bind to micro-tubules and stabilize them
What are presnillin?
multi pass transmembrane proteins that constitute the catalytic sub-units of gamma-secratase
PSEN1 -chromosome 14 encodes presenilin 1 (PS-1)
PSEN2 - chromosome 1 encodes presenilin 2
what does pimplikar 2010 say?
defects in ps1 leads to defective endo-lysosomal trafficking and proteolysis
What is the general job of ApoE
binds to soluble and aggregated AB and the job is to enhance the proteolytic breakdown of this peptide both within and between cells
isoform APOE4 isnt as effective as the others at promoing these reactions — increased vulnerability to AD in individuals with that gene variation
What are the different APOE isoforms?
ApoE4- doesnt bin AB effectively- less clearance
APoE2- neuroprotective
so therapeutically, increasing ApoE2 an ecreasing ApoE4
What does Candela et al 2010 say?
receptor of advanced glycoprotein end products RAGE transports AB back into the brain from the plasma and blocking this may be able to reduce AB toxicity
What does Leissring 2003 say?
talks about how there is less IDE and NEP in alzheimers
What does Regland 2001 say?
beta sheet production is facilitated by glycosaminoglycans therefore blocking this by the zinc/copper chelator clioquinol could reduce aggregation
What would blocking RAGE do?
blocks the transport of AB plaques from the plasma into the brain
What does sevigny 2016 say?
antibody aducanumab reduces AB plaques in AD
