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Neuropsychopharmacology > Molecular Mechanisms of Alzheimers Disease > Flashcards

Molecular Mechanisms of Alzheimers Disease Flashcards

1
Q

What is dementia?

A

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

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2
Q

What does dementia affect?

A

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

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3
Q

What is vascular dementia?

A

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

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4
Q

What are the main types of dementia?

A

60-75% - Alzheimers

20% - Vascular

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5
Q

What are the pathophysiological features inside the Alzheimers brain?

A 
severe cell loss
protein accumulations
inflammation
oxidative damage
spread from hippocampus right through brain into cerebellum and into the spinal cord
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6
Q

What are the genetic links with LOAD?

A

ApoE

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7
Q

What are the genetic links with EOAD?

A

APP, PSEN1, PSEN2

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8
Q

What is ApoE?

A

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

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9
Q

Where is ApoE secreted?

A

the glial cells in nascent HDL-like particles

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10
Q

What is the concentration of ApoE in the CSF?

A

5micrograms/ml

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11
Q

What is the role of ApoE?

A

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

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12
Q

What are the receptors for ApoE?

A

LDLR and LRP1

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13
Q

Which ApoE receptor has a faster endocytosis rate?

A

LRP1

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14
Q

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

A

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

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15
Q

What are the risk factors associated with ApoE4?

A

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

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16
Q

What is the ApoE4 genotype assciated with?

A 
more extensive plaques and tangles
high CSF concentrations of soluble Ab
impaired synaptic plasticity
increased hippocampal atrophy
more brain inflammation
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17
Q

What is the role of ApoE in amyloid removal?

A

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

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18
Q

How does ApoE4 slow down the removal of Ab?

A

switches clearance from LRP1 to VLDLR slowing internalisation and removal

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19
Q

How does ApoE facilitate removal of Ab?

A

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

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20
Q

What enzyme helps clear Ab?

A

neprilysin

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21
Q

What are potential methods of targetting ApoE4?

A

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

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22
Q

What are the risk genes in LOAD?

A

TREM2 - increases 3-fold, also associated with PD

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

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23
Q

What are the risk mutations in EOAD?

A

APP
PSEN1
PSEN2

24
Q

What is the effect of APP?

A

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

25
Q

What is the effect of PSEN1 and PSEN2?

A

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

26
Q

How does APP alter the amount of Ab produced?

A

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

27
Q

What is the cholinergic hypothesis?

A

loss of the cholinergic projections from NBM to cortex and hippocampus

28
Q

How is neuronal degeneration supported by the cholinergic hypothesis?

A

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

29
Q

What is the therapeutic intervention methods for the cholinergic hypothesis?

A

muscarinic receptor antagonists, AChEIs

30
Q

What are the current therapies associated with the cholinergic hypothesis?

A

Tacarine
Donepizil
Rivastigmine
Galantamine

31
Q

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

A

effects are temporary

only 40% of patients respond to treatment

32
Q

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

A

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

33
Q

What is the result of the glutamate/calcium dysregulation

A

Tau phosphorylation and neuronal death

34
Q

What survival pathway is inhibited by glutamate?

A

CAMK II, ERK, pCREB

35
Q

What is the current treatment affecting the glutamate hypothesis?

A

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

36
Q

What is the Amyloid Hypothesis?

A

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

37
Q

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

A

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

38
Q

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

A

Ab-oligomerisation inhibitors
selective amyloid lowering agents
tau aggregation inhibitors

39
Q

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

A

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

40
Q

What are the current drugs being trialled for amyloid processing?

A

a-secretase induce
y-secretase inhibitor
BACE - inhibitors

41
Q

What is the Tau hypothesis?

A

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

42
Q

What is the current treatment for the Tau hypothesis?

A

Using Methylene blue prevents aggregation - in P3 trial

43
Q

How does the brain normally neutralise free radicals?

A

Glutathione system
Superoxide dismutase
Catalase

44
Q

What can oxidative stress be caused by?

A

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

45
Q

What are the problems with antioxidant treatment?

A

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

46
Q

What is interesting about people with arthritis?

A

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

47
Q

What are the new targets in the treatment of AD?

A

Humanin

a7nAChRs

48
Q

What is significant about a7AChRs?

A

Ab induces the expression

49
Q

What happens upon activation of a7nAChRs?

A

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

50
Q

What are the interactions of a7nAChRs with Ab?

A

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

51
Q

What are the potential therapeutics targeting nAChRs?

A

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

52
Q

How are mice modelled in AD?

A

Use of AD mice with swedish mutation

Use of Odor Span Task

53
Q

What are the features of the Tg2576 mouse model?

A 
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
54
Q

What is humanin?

A

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

55
Q

What is significant about humanin expression?

A

co-expresses with amyloid as an early biomarker for AD

56
Q

Where is Humanin produced?

A

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

Neuropsychopharmacology (8 decks)

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