L9 - Alzeimer's Flashcards Preview

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Flashcards in L9 - Alzeimer's Deck (37):
1

What are the symptoms of Alzheimer's?

Forgetfulness
Confusion
Less movement
Loss of bodily function

2

What is the neuroanatomy of an Alzheimer's patient?

Layers of neurons get thinner, big gaps in cortex

3

What did PET scans of someone going through Alzheimer's show?

Loss of energy metabolism around brain

4

What are the cellular changes in Alzheimer's?

Beta- Amyloid plaques
tau tangles

5

Where does tau build up?

Cortex
Hippocampus
Visual cortex

6

what does tau normally do?

Helps stabilise microtubules and axon transport

7

What can indirectly cause hyperphosphorylisation of tau?

Oxidative stress

8

What direct events can cause the hyper-phos of tau

Upregulating of tau kinases
Downreg of phosphatases
Mutations

9

What does the LOF of tau cause?

Detachment of MT

10

What can the GOF of tau cause?

NFTs made of hyperphosphorylated tau sequester normal tau.
NFTs become physical obstacles of vesicles

11

How does tau normally function?

Gets in the way of cargo but is required for MT integrity
Usually dephosphorylated to move out the way for motor proteins

12

What do tau-P mutations cause?

More readily phosphorylated and lead to neurodegeneration

13

What first suggests the amyloid hypothesis exists?

Down's syndrome leads to AD by 40, linked to chr 21

14

What other proteins could affect tau phosphorylation?

GSK3, CDK5 AND MARK

15

What happened when amyloid-Beta was synthesised and put into cultures?

Toxic to neuronal cultures

16

What other 2 genes were found to be associated with early onset AD>

Prenenilin 1 and 2

17

What did mutations in prenelinin cause?

Increased production of amyloid beta

18

What do the presenilins code for?

Two secretases beta (BACE) and gamma wich process beta-amyloid prescursor protein

19

How is the proteolysis of APP involved?

After APP produced it either produces neurtrophic, neuroprotective peptide or produces AB peptide
Depending on which secretase chops it first it can be good or bad

20

What happens when alpha-secretase (ADAM) cuts first and what happens when BACE doe?

ADAM - beneficial
BACE - not good and impairs function

21

How does cell-cell spread of amyloid-B happen?>

Produced exracellularly and wraps up in little vesicles which are taken up by other cells - propensity for damage to spread around the brain like a prion

22

What was shown in animal models for a therapy for amyloid hypo and what is the problem with it?

Inhibitor of B-secretase reduced about of Ab being produced
Work agains many other proteins

23

What has been suggested as another therapy for amyloid hypo?

Proteolysis of amyloid-b

24

Why are amploid plaques so bad?

Form clumps and hen attract other molecules and becomes resistant to degredation

25

What eznymes could be invovled in therapeutic degradation of amyloid?

Neprylysin and insulin degrading enzyme

26

What does neprilysin do?

Breaks down oligomers and breaks down into fragments

27

What do amyloid-b plaques do?

Might bind to post synaptic receptors affecting transmission

28

How do the amyloid and tau hypos mix?

Need interaction between Ab and tau to make MT transport work?
May form complexs

29

What do plaques and tau tangles cause in neurons

Dendritic degradation

30

What is a gene associated with lae onset AD?

aPOLIPOROTEIN e - many variants with differing levels of death

31

Which variants of apolipoprotein E are the best and worst?

2 and 3 are good, 4 is bad

32

What is proposed to be the fuction of apolipoprotein E?

Clearance of cholesterol and possibly amyloid B and take it to blood

33

How could AD be linked to alzeimers>

May be to do with clearance of cholesterol
Mutations in insulin signalling increases risk of dementia

34

What is Liraglutide?

Diabetic drug that preserves mouse memory

35

How is oxidative stress suggested to be linked to AD?

Amyloid-B possibly protects cells for ROS?
(with diabetes) = problems with sugar and fat metabolism puts stress on mitochondria

36

How vaccination go with trying to help AD?

370 patients got inflammation of the meninges - microglia and t cells attacked the Ab42 vaccination
7 years later had lower amyloid b
Clinical trials of shorter peptides (long end was attacked)

37

What is the cholinergic drug hypo?

Using inhibitors of ACh-esterase so ACh sits in synapses longer
Can be good, some useless