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PA40160 seminars > Alzheimer's Disease > Flashcards

Alzheimer's Disease Flashcards

1
Q

What are the 4 characteristic brain hallmarks of alzheimer’s disease?

A

Amyloid beta plaques
Neurofibrillary Tau tangles
Inflammation
Glycation

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2
Q

What part of the brain does AD start in?

A

Lateral enterorhinal cortex

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3
Q

What regions does AD spread to after the lateral enterorhinal cortex?

A

cortical regions like the parietal cortex

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4
Q

What happens to the brain in AD?

A

Shrinks and loses grey matter.
Shutdown in brain metabolism and loss of activity.
(brain atrophy)

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5
Q

How many amino acids long are Abeta plaques?

A

42

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6
Q

What is Tau part of?

A

the cytoskeleton- the microtubule stabilising protein

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7
Q

What are the microglia?

A

Resident brain macrophages. The immune cells in the brain

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8
Q

What do microglia do?

A

Clean up damaged neurones

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9
Q

Are advanced glycation end products intra or extra cellular?

A

Extracellular

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10
Q

What do advanced glycation end products reflect?

A

Sugar modification and oxidation through radical type damage of proteins in the brain

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11
Q

98% of AD cases are what?

A

Sporadic

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12
Q

Sporadic AD cases have an age of onset of what?

A

> 65 years

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13
Q

Carrying one copy of ApoE4 allele increases your risk of AD by what?

A

4 times

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14
Q

ApoE2 allele increases your risk of AD or protects you?

A

Gives you protection

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15
Q

Genetic forms of AD account for what % of the population?

A

less than 1%

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16
Q

What types of neurones are lost in AD?

A

Cholinergic

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17
Q

Is the presynaptic or postsynaptic side of the neurone lost first?

A

Presynaptic

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18
Q

What is the therapeutic idea with regards to cholinergic neurones?

A

Maintain acetylcholine in the synapse

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19
Q

How is acetylcholine maintained in the synapse?

A

By blocking acetylcholinesterase

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20
Q

What are the three acetykcholinesterase inhibitors?

A

Aricept (donepezil hydrocholride)
Exelon (rivastigmine)
Reminyl (galantamine)

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21
Q

Acetylcholinesterase inhibitors are recommended for what form of AD?

A

Mild to moderate

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22
Q

what percentage of individuals show some benefit from acetylchilinesterase inhibitors for a limited amount of time?

A

50-60%

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23
Q

What is Ebixa (memantine)?

A

NMDA receptor antagonist

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24
Q

What type of AD is memantine recommended for?

A

Moderate to severe

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25
Q

What system does Ebixa (memantine) target?

A

Glutamate

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26
Q

What are glutamate ion channels important in?

A

Memorry

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27
Q

Over activation of glutamate ion channels is associated with what?

A

Brain damage

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28
Q

What does Ebixa (memantine) mimick?

A

Magnesium

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29
Q

What removes Ebixa (memantine) from the glutamate ion channel?

A

Action potential (not background activity)

30
Q

Why is it important that Ebixa (memantine) doesn’t permanently block glutamate channels?

A

They are needed for brain cognition and memory

31
Q

What is the problem with MK-801?

A

It is not thrown out by synaptic activity so causes a global blockade. Side effects outweighed the benefits.

32
Q

Os a combination of ChEI and Memantine prescribed routinely anywhere?

A

No

33
Q

What do ChEI and Memantine do?

A

ChEI return signalling towards normal

Memantine reduces the background noise

34
Q

What is the first step of the emyloid cascade hypothesis?

A

Changes in AB metabolism

  • increase in total AB production
  • increase in the Ab42/AB40 ratio
  • reduced AB degradation/clearance
35
Q

What happens after the initial changes in AB metabolism?

A

Oligomerisation of AB42 and initial AB42 deposits

36
Q

What are the main steps of Amyloid cascade hypothesis?

A

Changes in AB metabolism
Oligomerisation and deposition of AB42 deposits
Inflammatory response
Neuronal injury
Oxidative injury
Oligomerisation and hyperphosphorylation of tau
Cell death associated with NT deficits

37
Q

What happens if APP is cut by a-secretase?

A

No amyloid beta formation

38
Q

What happens if APP is cut by b-secretase?

A

Leads to amyloid beta peptides

39
Q

Where do almost all of the mutations in APP sit?

A

At or alongside the beta-secretase cleavage site

40
Q

Where do all the familial mutations lie?

A

Gama-secretase

41
Q

What is Semagacestat (LY450139)?

A

Y-secretase inhibitor

42
Q

Why was the phase 3 trial for Semagacestat halted?

A

Failed to slow disease progression, made cognition worse and increased the risk of skin cancer

43
Q

What is Verubecestat (MK-8931)?

A

B-Secretase inhibitor

44
Q

What do initial phase 1 studies report for Verubecestat?

A

Reductions in AB40, !B42 and sAPPB in the CSF

45
Q

What is the theory behind the use of anti-AB antibodies?

A
  • Plaque breakdown
  • Peripheral sink
  • Aggregation inhibitor
46
Q

How does plaque breakdown occur with anti-AB antibodies?

A

Plaques are destroyed through Fc-mediated phagocytosis by microglia

47
Q

How does the peripheral sink occur with anti-AB antibodies?

A

The formation of antigen-antibody complexes in the periphery sequesters amyloid away from the brain

48
Q

How does ‘aggregation inhibition’ occur with anti-AB antibodies?

A

Formation of antigen-antibody complexes prevents amyloid beta from accumulating in plaques.

49
Q

What are the two forms of active immunisation?

A

Immunisation with intact AB42 peptide

Immunisation with AB fragments

50
Q

What is passive immunisation?

A

Immunisation with anti-AB antibodies

51
Q

What type of immunisationis AN1792?

A

Active

52
Q

What is AN1792?

A

Aggregated synthetic human AB1-42

53
Q

Why was the AN1792 trial halted?

A

18 patients developed meningoencephalitis

54
Q

What was the AN1792 trial result?

A

Halted due to meningoencephalitis,
Clearance of cortical amyloid plaques
No clear evidence of clinical response

55
Q

What type of immunisation is Bapineuzumab?

A

Passive

56
Q

What is Bapineuzumab?

A

A monoclonal humanised antibody which recognises AB1-5

57
Q

What was the outcome of Bapuneuzumab?

A

Reduction in cerebral AB load

Limited evidence of clinical benefit

58
Q

What type of immunisation is Solanezumab?

A

Passive

59
Q

What is Solanezumab?

A

A humanised monocloncal antibody which preferentially binds to soluble forms of AB (AB13-28)

60
Q

What did the Solanezumab trial fail?

A

Failed to reach endpoints

61
Q

What type of immunisation is Aducanumab?

A

Passive

62
Q

What is Aducanumab?

A

A human monoclonal antibody

63
Q

What do mutations in Tau lead to?

A

Fronto-Temporal Dementia

64
Q

Why is Tau better for targeting than AB?

A

It correlates much better with the appearance of symptoms

65
Q

What is Rember?

A

Tau aggregation inhibitor

66
Q

What are two drugs which target tau pathology?

A

Rember

GSK3B inhibitors

67
Q

What adverse effect did GSK3B inhibitors cause?

A

Liver toxicity

68
Q

How do we reduce tau pathology?

A

Inhibit phosphorylation

69
Q

What was the outcome of the trials for the first drug to target tau tangles?

A

Reduced brain shrinkage

Scores on cognition and performance significantly improved

70
Q

What are the 6 targets for disease progression?

A 
Amyloid beta
Tau
Unfolded protein response
Oxidative stress
Apoptosis
Inflammation
71
Q

When do AB changes occur?

A

10/20 years before you see any symptoms

72
Q

What evidence is there that we have the wrong target for drugs (AB)?

A

AB observed in non demented brains.

AB vaccination cleared plaques but no cognitive benefit.

PA40160 seminars (2 decks)

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