Molecular Mechanisms of Alzheimers Disease

Question 1

What is dementia?

Answer 1

a syndrome of a chronic or progressive natures in which there is deterioration of function beyond what might be expected from normal aging

Question 2

What does dementia affect?

Answer 2

learning, memory, thinking, orientation, comprehension, language and judgement

Question 3

What is vascular dementia?

Answer 3

step wise deficits in the ability due to small strokes in the area that was affected

Question 4

What are the main types of dementia?

Answer 4

60-75% - Alzheimers

20% - Vascular

Question 5

What are the pathophysiological features inside the Alzheimers brain?

Answer 5

severe cell loss
protein accumulations
inflammation
oxidative damage
spread from hippocampus right through brain into cerebellum and into the spinal cord

Question 6

What are the genetic links with LOAD?

Answer 6

ApoE

Question 7

What are the genetic links with EOAD?

Answer 7

APP, PSEN1, PSEN2

Question 8

What is ApoE?

Answer 8

apolipoprotein is a major component of VLDL found in the brain and liver, that remove excess cholesterol from the blood and carry it to the liver for processing

Question 9

Where is ApoE secreted?

Answer 9

the glial cells in nascent HDL-like particles

Question 10

What is the concentration of ApoE in the CSF?

Answer 10

5micrograms/ml

Question 11

What is the role of ApoE?

Answer 11

to deliver cholesterol and lipid to the neurons and in reverse cholesterol transport to the blood
as a ligand in receptor mediated endocytosis of lipoprotein particles in the CNS

Question 12

What are the receptors for ApoE?

Answer 12

LDLR and LRP1

Question 13

Which ApoE receptor has a faster endocytosis rate?

Answer 13

LRP1

Question 14

What are the three different forms of ApoE and what are their different amino acids?

Answer 14

ApoE2 - cys 112, cys 158 - 8%
ApoE3 - cys 112, arg 158 - 77%
ApoE4 - arg 112, arg 158 - 15%

Question 15

What are the risk factors associated with ApoE4?

Answer 15

atherosclerosis, CAA, tauopathies, DLB, PD, MS, AD

Question 16

What is the ApoE4 genotype assciated with?

Answer 16

more extensive plaques and tangles
high CSF concentrations of soluble Ab
impaired synaptic plasticity
increased hippocampal atrophy
more brain inflammation

Question 17

What is the role of ApoE in amyloid removal?

Answer 17

ApoE containing particules sequester Ab and modulate the cellular uptake of an ApoE-Ab complex by receptor mediated endocytosis
glial = protective, neuronal = toxic

Question 18

How does ApoE4 slow down the removal of Ab?

Answer 18

switches clearance from LRP1 to VLDLR slowing internalisation and removal

Question 19

How does ApoE facilitate removal of Ab?

Answer 19

facilitates the binding and internalisation or clearance by enzymes such as neprilysin

Question 20

What enzyme helps clear Ab?

Answer 20

neprilysin

Question 21

What are potential methods of targetting ApoE4?

Answer 21

Conversion of E4 to E3 by small MW structure correction
Increase lipidation of E4
Ab decoy proteins interfering wiht ApoE4 and Ab interaction
ApoE4 antibodies
ApoE mimetic peptides reversing effects of ApoE4
Gene transfer of ApoE2 in place of E4

Question 22

What are the risk genes in LOAD?

Answer 22

TREM2 - increases 3-fold, also associated with PD

PLD 3 - over-expression leads to reduction in Ab levels

Question 23

What are the risk mutations in EOAD?

Answer 23

APP
PSEN1
PSEN2

Question 24

What is the effect of APP?

Answer 24

increases Ab 2-3x by altering the cleavage efficiency of b-secretase - Swedish Mutation

Question 25

What is the effect of PSEN1 and PSEN2?

Answer 25

components of y-secretase which cleaves APP into Ab fragments PSEN 1- chromosome 14 and PSEN 2 on chromosome 1

Question 26

How does APP alter the amount of Ab produced?

Answer 26

a-secretase cleaves leaving Ab 1-40 which is neuroprotective BACE-1 cleaves at a higher point leaving Ab 1-42 which aggregates forming plaques and killing neurons Swedish mutation alters affinity for BACE 1 resulting in more Ab 1-42

Question 27

What is the cholinergic hypothesis?

Answer 27

loss of the cholinergic projections from NBM to cortex and hippocampus

Question 28

How is neuronal degeneration supported by the cholinergic hypothesis?

Answer 28

loss of Choline Acetyltranferase (ChAT) reduction in presynaptic choline transporter reduction in NBM cholinergic neurons

Question 29

What is the therapeutic intervention methods for the cholinergic hypothesis?

Answer 29

muscarinic receptor antagonists, AChEIs

Question 30

What are the current therapies associated with the cholinergic hypothesis?

Answer 30

Tacarine Donepizil Rivastigmine Galantamine

Question 31

What is the problem with the current therapies associated with the cholinergic hypothesis?

Answer 31

effects are temporary | only 40% of patients respond to treatment

Question 32

What is the theory behind the glutamate/calcium dysregulation hypothesis?

Answer 32

Ab oligomers enhance glutamate release and block uptake by astrocytes through EAAT - glutamate transporters Glutamate in cleft increases activating NMDA receptors and increasing Ca influx which activates pathways for neuronal shrinkage and synaptic loss

Question 33

What is the result of the glutamate/calcium dysregulation

Answer 33

Tau phosphorylation and neuronal death

Question 34

What survival pathway is inhibited by glutamate?

Answer 34

CAMK II, ERK, pCREB

Question 35

What is the current treatment affecting the glutamate hypothesis?

Answer 35

Memantine - voltage dependent, non-competitive NMDA receptor antagonist used for moderate AD or those who cannot take AChEIs

Question 36

What is the Amyloid Hypothesis?

Answer 36

Ab - generation causing oxidation, excitotoxicity, aggregation, inflammation and tau

Question 37

What are the potential therapeutic strategies involving the preventing of Ab 1-42 production?

Answer 37

preventing Ab 1-42 production by potentiating a-secretase, or inhibiting b/y secretases

Question 38

What are the potential therapeutic strategies involving the prevention of aggregation?

Answer 38

Ab-oligomerisation inhibitors selective amyloid lowering agents tau aggregation inhibitors

Question 39

What are the potential therapeutic strategies involving promoting removal of Ab?

Answer 39

vaccines - however have had to stop due to strokes and death as a result of blood vessel ruptures

Question 40

What are the current drugs being trialled for amyloid processing?

Answer 40

a-secretase induce y-secretase inhibitor BACE - inhibitors

Question 41

What is the Tau hypothesis?

Answer 41

the highly soluble, microtubule binding protein is hyperphosphorylated, destabilising microtubules causing impairments in axonal transport and neuronal dysfunction

Question 42

What is the current treatment for the Tau hypothesis?

Answer 42

Using Methylene blue prevents aggregation - in P3 trial

Question 43

How does the brain normally neutralise free radicals?

Answer 43

Glutathione system Superoxide dismutase Catalase

Question 44

What can oxidative stress be caused by?

Answer 44

aging, food contaminents, environmental pollutio, cigarettes, amyloid, inflammation and injury

Question 45

What are the problems with antioxidant treatment?

Answer 45

VitC does not cross blood brain barrier Vit E is tightly regulated in the brain Only 3/24 clinical trials have yielded successful results

Question 46

What is interesting about people with arthritis?

Answer 46

Less likely to get AD NSAIDs - didn't prevent onset Statins aren't tested yet

Question 47

What are the new targets in the treatment of AD?

Answer 47

Humanin | a7nAChRs

Question 48

What is significant about a7AChRs?

Answer 48

Ab induces the expression

Question 49

What happens upon activation of a7nAChRs?

Answer 49

facilitates neurotransmission and synaptic plasticity induces LTP supports learning and memory improves attention and memory

Question 50

What are the interactions of a7nAChRs with Ab?

Answer 50

found in amyloid plaques has extremely high affinity for Ab can mediate the internalisation of Ab and inflammatory response blocks amyloid toxicity

Question 51

What are the potential therapeutics targeting nAChRs?

Answer 51

agonists - rapid desensitisation but cognitive enhancing and anti-inflammatory antagonists - block adverse effects of Ab on accumulation and toxicity, not enhancing and block synaptic plasticity

Question 52

How are mice modelled in AD?

Answer 52

Use of AD mice with swedish mutation | Use of Odor Span Task

Question 53

What are the features of the Tg2576 mouse model?

Answer 53

``` APP gene 10months show learning difficulties 1 year - some plaques 15-18months - like human brain Struggled with Odor Span Task from 4 months Nicotine improved learning ```

Question 54

What is humanin?

Answer 54

24aa peptide only found in AD brain which protects against toxicity and is neuroprotective in stroke models

Question 55

What is significant about humanin expression?

Answer 55

co-expresses with amyloid as an early biomarker for AD

Question 56

Where is Humanin produced?

Answer 56

made by mitochondria to be exported to neighbouring cells and protects against amyloid toxicity