Molecular Biology of Alzheimer's

Question 1

what is the amyloid cascade hypothesis

Answer 1

APP (amyloid precursor protein) and amyloid beta cause AD

Question 2

what two things can amyloid beta peptide turn into?

Answer 2

aggregate into senile plaques
neurotoxic ADDL oligomers

Question 3

what is the primary pathology of AD

Answer 3

senile plaques
neurofibillary tangles

Question 4

what are the secondary changes of AD pathology

Answer 4

neuronal loss
synaptic degradation
glial activation (inflammation)
vascular pathology (blood vessels)

Question 5

outline senile plaques

Answer 5

made of amyloid beta 40-42aa peptide
extracellular protein aggregate
cause synaptic disruption

Question 6

why are downs syndrome and AD linked?

Answer 6

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

Question 7

outline amyloid precursor protein

Answer 7

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

Question 8

what happens if a transgenic mouse is injected with APP?

Answer 8

develops amyloid deposits and tau pathology
shows memory deficits

Question 9

how is the APP protein cleaved

Answer 9

by two secretase enzymes
beta secretase
gamma secretase
this creates amyloid
which then forms amyloid beta plaques and ADDLs

Question 10

does generation of amyloid beta occur in non AD people?

Answer 10

yes - but this amyloid is created by cleaving APP with alpha secretase enzyme and not beta or gamma
majority is produced in this way

Question 11

what are the two alpha secretase enzymes which cleave APP in the ‘good pathway’

Answer 11

ADAM10 and TACE

Question 12

how can we increase decrease the likelihood of beta secretase forming amyloid beta?

Answer 12

increase amount of alpha secretase enzymes
e.g Talsaclidine - acts on muscarinic M1 receptor to increase alpha but doesnt know improvement in cognition

Question 13

what is alpha secretase activity dependant on and what study showed this?

Answer 13

cholesterol
rabbits treated with high fat diet developed senile plaques

Question 14

how do beta and gamma secretase cut APP

Answer 14

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

Question 15

how much of AD is familial

Answer 15

10%

Question 16

what do genetic mutations in familial AD do to the enzymes?

Answer 16

mutations in APP around beta-amyloid sequence make APP a better substrate for beta and gamma secretase enzymes

Question 17

what does ADDL stand for

Answer 17

amyloid-beta derived diffusible ligands

Question 18

outline ADDLs

Answer 18

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

Question 19

why do researchers think ADDLs are the actual toxic component of AD as opposed to senile plaques

Answer 19

transgenic mice which produce excessive amounts of amyloid beta, show memory impairment before senile plaques appear in the brain

Question 20

what did Schenk et al 1999 find in AD mice

Answer 20

immunisation of mice with amyloid beta peptide lead to them having reduced deposition of senile plaques in the brain

Question 21

how did immunisation work in humans?

Answer 21

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

Question 22

what are the two gene mutations associated with AD and what do they do

Answer 22

presenilin - PSEN1 and PSEN2
make gamma secretase more active (cluster around membrane domain) to increase amyloid beta production this way

Question 23

how does presenilin exist?

Answer 23

large complex with other proteins
located in endoplasmic reticulum and trans golgi network
cell surface location

Question 24

what does the gamma secretase presenilin complex do

Answer 24

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

Question 25

what is the Notch phenotype

Answer 25

cleavage of Notch by presenilin mutation gives vascular and developmental abnormalities
as gamma secretase/presenilin are involved in notch signalling

Question 26

outline gamma secretase/presenilin inhibition

Answer 26

because they are involved in notch signalling, may lead to tumour formation

Question 27

what is the evidence that inflammation is involved in AD?

Answer 27

rheumatoid arthiritis patients are at reduced risk of AD
patients on anti-inflammatories show reduced AD
even ibuprofen can inhibit gamma secretase/presenilin

Question 28

how often does pathogenic cleavage of APP by beta and gamma secretase happen?

Answer 28

less than 5% of the time

Question 29

outline apolipoprotein E gene (APOE)

Answer 29

normal function - transporting cholesterol around the body
produced in brain by astrocytes
common gene allele is e3
e4 allele is a risk factor - those who carry one or more are at increased risk of AD
necessary for neuronal repair

Question 30

outline APOE e4 allele in AD

Answer 30

contributes to familial and sporadic AD
affects onset age e.g person with 2 e4 develops AD at 65, with one develops at 75 and without allele at 85
might increase amount of pathology in the brain 2 e4 = 20% more pathology
quicker death due to faster rate of decline

Question 31

how does APOE act on amyloid beta

Answer 31

like a glue causing acceleration of amyloid beta aggregation

Question 32

what happens in transgenic mouse if you remove APOE

Answer 32

fails to develop amyloid pathology

Question 33

how is amyloid beta normally degraded in the brain?

Answer 33

very effectively via several enzymes e.g Neprilysin , IDE, ECE-1