L9 - Alzeimer's

Question 1

What are the symptoms of Alzheimer’s?

Answer 1

Forgetfulness
Confusion
Less movement
Loss of bodily function

Question 2

What is the neuroanatomy of an Alzheimer’s patient?

Answer 2

Layers of neurons get thinner, big gaps in cortex

Question 3

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

Answer 3

Loss of energy metabolism around brain

Question 4

What are the cellular changes in Alzheimer’s?

Answer 4

Beta- Amyloid plaques

tau tangles

Question 5

Where does tau build up?

Answer 5

Cortex
Hippocampus
Visual cortex

Question 6

what does tau normally do?

Answer 6

Helps stabilise microtubules and axon transport

Question 7

What can indirectly cause hyperphosphorylisation of tau?

Answer 7

Oxidative stress

Question 8

What direct events can cause the hyper-phos of tau

Answer 8

Upregulating of tau kinases
Downreg of phosphatases
Mutations

Question 9

What does the LOF of tau cause?

Answer 9

Detachment of MT

Question 10

What can the GOF of tau cause?

Answer 10

NFTs made of hyperphosphorylated tau sequester normal tau.

NFTs become physical obstacles of vesicles

Question 11

How does tau normally function?

Answer 11

Gets in the way of cargo but is required for MT integrity

Usually dephosphorylated to move out the way for motor proteins

Question 12

What do tau-P mutations cause?

Answer 12

More readily phosphorylated and lead to neurodegeneration

Question 13

What first suggests the amyloid hypothesis exists?

Answer 13

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

Question 14

What other proteins could affect tau phosphorylation?

Answer 14

GSK3, CDK5 AND MARK

Question 15

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

Answer 15

Toxic to neuronal cultures

Question 16

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

Answer 16

Prenenilin 1 and 2

Question 17

What did mutations in prenelinin cause?

Answer 17

Increased production of amyloid beta

Question 18

What do the presenilins code for?

Answer 18

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

Question 19

How is the proteolysis of APP involved?

Answer 19

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

Question 20

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

Answer 20

ADAM - beneficial

BACE - not good and impairs function

Question 21

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

Answer 21

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

Question 22

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

Answer 22

Inhibitor of B-secretase reduced about of Ab being produced

Work agains many other proteins

Question 23

What has been suggested as another therapy for amyloid hypo?

Answer 23

Proteolysis of amyloid-b

Question 24

Why are amploid plaques so bad?

Answer 24

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

Question 25

What eznymes could be invovled in therapeutic degradation of amyloid?

Answer 25

Neprylysin and insulin degrading enzyme

Question 26

What does neprilysin do?

Answer 26

Breaks down oligomers and breaks down into fragments

Question 27

What do amyloid-b plaques do?

Answer 27

Might bind to post synaptic receptors affecting transmission

Question 28

How do the amyloid and tau hypos mix?

Answer 28

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

Question 29

What do plaques and tau tangles cause in neurons

Answer 29

Dendritic degradation

Question 30

What is a gene associated with lae onset AD?

Answer 30

aPOLIPOROTEIN e - many variants with differing levels of death

Question 31

Which variants of apolipoprotein E are the best and worst?

Answer 31

2 and 3 are good, 4 is bad

Question 32

What is proposed to be the fuction of apolipoprotein E?

Answer 32

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

Question 33

How could AD be linked to alzeimers>

Answer 33

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

Question 34

What is Liraglutide?

Answer 34

Diabetic drug that preserves mouse memory

Question 35

How is oxidative stress suggested to be linked to AD?

Answer 35

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

Question 36

How vaccination go with trying to help AD?

Answer 36

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)

Question 37

What is the cholinergic drug hypo?

Answer 37

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