Alzheimers

Question 1

Define alzheimers

Answer 1

irreversibly progressive neurodegenerative disease that starts in the temporal lobe and progresses to anterior and posterior lobes resulting in interference of daily functioning

Question 2

What is the Pathophysiology of Alzheimers?

Answer 2

Plaques- beta-amyloid proteins which are extracellular and tangles - hyper-phosphorylated tau proteins which are intracellular
Both are insoluble

Question 3

Talk about the APP protein

Answer 3

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

Question 4

what are the genes implicated in BA plaques?

Answer 4

APP
PS1(most common)
PS2
APOE4

Question 5

Talk about the APP protein and what the secratases do to it?

Answer 5

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

Question 6

what does Johnson et al 2012 say?

Answer 6

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

Question 7

What effects does presinillin have on the beta amyloid plaques?

Answer 7

causes incomplete digestion (loss of function) of the beta amyloid plaques , therefore increase in beta amyloid plaques

Question 8

What is protective against the beta amyloid toxicity?

Answer 8

vitamin E and oestrogen are protective

Question 9

Talk about the three secratases

Answer 9

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

Question 10

Talk about the transformation of beta amyloid from monomers to amyloid plaques

Answer 10

this is facilitated by zinc/copper

Question 11

How does AB plaques cause alzheimers disease?

Answer 11

induces apoptosis in cells some of which may be inducing ROS production
insertion into cell membranes and disrupt integrity
may promote tau aggregation

Question 12

What are neurofibrillary tangles?

Answer 12

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

Question 13

Discuss the phosphorylation of Tau

Answer 13

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

Question 14

What are the three different isoforms of ApOE protein?

Answer 14

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

Question 15

How does APOE proteins exert their actions?

Answer 15

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

Question 16

What mediates the influx of AB Peptides across the BBB to the brain?

Answer 16

RAGE

Question 17

In alzheimers name some loss of function mutations

Answer 17

IDE- degrades soluble oligomers intracellularly

NEP- degrades extracellular plaques

Question 18

How does APOE influence the clearance of AB?

Answer 18

AB clearance ecreases because AB may have lower affinity for APOE4 or oligomerization because AB may have increase affinity for APOE4

Question 19

What is the multifactorial threshold model?

Answer 19

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

Question 20

which gene is implicated in late onset alzheimers?

Answer 20

ApOE4

Question 21

What is the amyloid cascade hypothesis?

Answer 21

imbalance between the production and clearance
production- increase in familial alzheimers
clearance - increase in sporadic parkinsons??

Question 22

Name some acetylcholinestarse inhibitors and their mechanism of action

Answer 22

they prevent the breakdown of acetylcholine into choline and acetate so that there is more acetylcholine

galantamine, donepazil, rivastigmine

Question 23

How does memantine work?

Answer 23

its a selective extrasynaptic NMDAR antagonist

Question 24

How are future therapeutics aimed at targetting AB an preventing the formation?

Answer 24

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

Question 25

How are future therapeutics aimed at preventing aggregation?

Answer 25

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

Question 26

How are future therapeutics targetting the clearance of AB?

Answer 26

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

Question 27

Talk about Tau hypothesis

Answer 27

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

Question 28

What are presnillin?

Answer 28

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

Question 29

what does pimplikar 2010 say?

Answer 29

defects in ps1 leads to defective endo-lysosomal trafficking and proteolysis

Question 30

What is the general job of ApoE

Answer 30

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

Question 31

What are the different APOE isoforms?

Answer 31

ApoE4- doesnt bin AB effectively- less clearance APoE2- neuroprotective so therapeutically, increasing ApoE2 an ecreasing ApoE4

Question 32

What does Candela et al 2010 say?

Answer 32

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

Question 33

What does Leissring 2003 say?

Answer 33

talks about how there is less IDE and NEP in alzheimers

Question 34

What does Regland 2001 say?

Answer 34

beta sheet production is facilitated by glycosaminoglycans therefore blocking this by the zinc/copper chelator clioquinol could reduce aggregation

Question 35

What would blocking RAGE do?

Answer 35

blocks the transport of AB plaques from the plasma into the brain

Question 36

What does sevigny 2016 say?

Answer 36

antibody aducanumab reduces AB plaques in AD