williamson - amyloid disease

Question 1

alzheimers is a senile dementia, what does this mean

Answer 1

gets worse as you get older

Question 2

alzheimers is most commonly diagnosed by …

Answer 2

examination of brain after death

Question 3

what are the plaques made up of

Answer 3

amyloid beta

Question 4

inside the neuron you can often see neurofibrillary tangles. these are hyperphosphorylated versions of which protein

Answer 4

tau

Question 5

amyloid beta is cut out of a much longer protein. what is this longer protein called

Answer 5

APP

Question 6

which protease cuts in the middle of the amyloid beta sequence and therefore lowers the amount of it

Answer 6

alpha-secretase

Question 7

if APP is cut by b-secretase it creates an extracellular fragment and a transembrane fragment. the transmembrane fragment is then cut by…

Answer 7

gamma secretase

Question 8

APP is either cut by alpha or…

Answer 8

beta then gamma

Question 9

gamma secretase produces a peptide tha is either 40 or 42 residues long. which one is prone to aggregation and more toxic

Answer 9

1-42 AB

Question 10

what is early onset alzheimers caused by mutations in

Answer 10

presenilins 1 and 2

Question 11

what is the amyloid cascade hypothesis

Answer 11

that alzheimers is caused by overproduction of AB which collects into plaques and the plaques are in some way toxic

Question 12

strongest genetic risk factos for alzheimers is an allele of which protein

Answer 12

apolipoprotein E (ApoE4)

Question 13

what is the function of ApoE

Answer 13

transports cholesterol to neurons

Question 14

what is the most likely reason for the association of ApoE and alzheimers

Answer 14

ApoE helps to remove or breakdown AB and E4 allele is worse at it

Question 15

what are amyloid diseases

Answer 15

diseases where a naturally occuring protein unfolds, misfolds, aggregates and collects in fibrous plaques

Question 16

all proteins unfold occasionally so pretty much all proteins can form amyloid T/F

Answer 16

T

Question 17

what is systemic amyloid disease

Answer 17

when body produces excessive amounts of antibody light chains which accumulate as amyloid deposits in different tissues

Question 18

what are acute phase proteins and what is an example of one

Answer 18

proteins that are produced by the body to deal with inflammation. one example is serum amyloid A

Question 19

what does serum amyloid A do

Answer 19

recruits immune cells and transports cholesterol to the liver. . upregulated in chronic inflammations and therefore builds up. can produce amyloid deposits in kidney

Question 20

dialysis is used when kidneys fail. The normal function of the kidney is to filter the blood and remove harmful stuff. Dialysis uses external dialysis filters and does not remove what

Answer 20

proteins so proteins build up with long term dialysis

Question 21

what is an example of a protein that is not removed by dialysis and can lead to diseade

Answer 21

b2 microglobulin - a component of MHC class I
can lead to dialysis related amyloidogenesis

Question 22

diabetes patients tend to get amyloid deposits of IAPP in the islet cells. why

Answer 22

as a consequence of insulin resistance, the body responds by expression of more insulin. a hormone IAPP is expressed at the same time as inulin and about 100x more

Question 23

if the amyloid cascase hypothesis is true, what can we expect

Answer 23

the severity of alzheimers to be related to the number of plaques
- there isnt a strong relationship

Question 24

there isnt a strong relationship between severity of alzheimers and number of plaques. what is there a better relationship with

Answer 24

severity and number of neurofibrillary tangles

Question 25

why are there problems with animal models of alzheimers

Answer 25

in humans it takes around 60years to develop. is behaviour in a 16month old mouse the same thing?

Question 26

plaques seem to cause what

Answer 26

local inflammation

Question 27

by causing local inflammation plaques can cause the body to attack its own neurons and kill them. what does this stimulate

Answer 27

production of ROS

Question 28

there are lots of experiments to show that what are more toxic than mature fibrils

Answer 28

oligomers

Question 29

what is the current most popular theory for alzheimers

Answer 29

that the toxic species are the oligomers

Question 30

what is alzheimers characterised by

Answer 30

AB plaques and neurofibrillary tangles made of hyperphosphorylated tau

Question 31

many people think changes in amyloid beta causes changes in tau T/F

Answer 31

T

Question 32

what are the possible therapies for alzheimers (5)

Answer 32

``` stabilise off pathway oligomer prevent fibrilisation dissociate fibril refold aggregates get rid of aggregates ```

Question 33

the only current drugs for alzheimers affect what

Answer 33

neurotransmitters

Question 34

alzheimers causes death of neurons and loss of connections. therefore you can...

Answer 34

strengthen the signalling across the synapse especially cholinergic - Ie inhibitors of cholinesterase (cleaves acetyl choline) – makes signal last longer

Question 35

what is the problem in developing gamma secretase inhibitors

Answer 35

also cleaves signalling receptor notch involved in neural development, heart development and maturation of cells in various tissues -So gamma secretase would have effects all over the body unless you could deliver it specifically to the brain

Question 36

one idea was Immunise using AB(1-42) and get immune system to do work. what did this lead to

Answer 36

reduces amyloid plaques but 6% of patients developed meningoencephalitis

Question 37

If toxic species are oligomers maybe the best treatment is not to prevent aggregation but deliberately induce aggregation, to steer AB out of oligomers into “harmless” plaques T/F

Answer 37

T

Question 38

a surprising number of these drugs made symptoms worse

Answer 38

- Maybe ROS that cause problems – look for antioxidants | - Maybe not drug we want NSAID or polyphenols like EGCG (green tea)

Question 39

what is the second most common dementia

Answer 39

parkinsons

Question 40

what is parkinsons characterised

Answer 40

shaking of hands associated with rigidity in posture

Question 41

what genes are associated with parkinsone

Answer 41

-PARK8 - has something to do with maintenacne of dendrite structure -gene for alpha synuclein - function not clear

Question 42

alpha synuclein is intrinsically disordered. what does this mean

Answer 42

more likely to form amyloid because dont need to unfold first - lower energy barrier to forming amyloid

Question 43

there are no cures to parkinsons just drugs that improve the signalling eg L-DOPA. what is this

Answer 43

biosynthetic precursor to dopamine