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Stage 2: Ageing > Alzheimer's Disease > Flashcards

Alzheimer's Disease Flashcards

1
Q

What are the two key features of AD pathology?

A

1) Amyloid plaques (extracellular)
2) Neurofibrillary tangles
- These cause neuronal cell death

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2
Q

What is the main constituent of amyloid plaques?

A

Beta-amyloid (Aβ(1-42)) - short peptide which can aggregate derived from amyloid precursor protein (APP), a type 1 membrane spanning protein

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3
Q

What enzymes process APP to produce Aβ?

A

(β and γ) Secretase proteases

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4
Q

Describe the three types of secretases

A

1) α secretase - cleaves APP within the Aβ sequence so doesn’t produce Aβ
2) β secretase (BACE1) - cleaves APP at N terminus of Aβ sequence so produces Aβ (with γ secretase)
3) γ secretase - cleaves APP at C terminus of Aβ sequence so produces Aβ with β secretase but doesn’t produce Aβ with α secretase, contains presenilin (PSEN-1 or 2)

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5
Q

What are the products of APP processing by α and γ secretase (normally dominant)?

A

sAPPα, p3 and C terminus stump

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6
Q

What are the products of APP processing by β and γ secretase?

A

sAPPβ, Aβ and C terminus stump

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7
Q

What is another substrate of γ secretase involved in development?

A

NOTCH

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8
Q

What are neurofibrillary tangles?

A
  • Intraneuronal pathologies

- Aggregates of paired helical filaments (PHF)

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9
Q

What is the main constituent of PHF?

A

Tau

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10
Q

What is tau?

A
  • A microtubule associated protein which stabilises microtubules through binding to tubulin esp. in axons
  • It is regulated by phosphorylation and in adults is less phosphorylated so that it sticks tighter to microtubules and prevents them from being more dynamic
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11
Q

What happens to tau in AD?

A
  • Tau is abnormally hyperphosphorylated in AD making it aggregate like Aβ
  • This may lead to detachment of tau from microtubules, destabilisation of microtubules, loss o microtubules and damage to axonal morphology and transport
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12
Q

What are the two kinases that phosphorylate tay in AD?

A

GSK3β and NCDK-5/p35

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13
Q

What autosomal dominant mutations can cause early onset (40s-50s) familial AD?

A

Mutations in genes that code for APP (clustered around Aβ sequence, inhibit α secretase and enhance β secretase and Aβ42 production by γ secretase), PSEN-1 and PSEN-2 (increase Aβ species)

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14
Q

What is the link between Down’s syndrome and AD?

A
  • Duplication of APP gene causes familial AD bc excess Aβ
  • Down’s syndrome patients develop typical AD pathology (plaques and tangles) in their 40s bc APP gene resides on chromosome 21
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15
Q

What are the actions of the APP mutations?

A
  • Increase total Aβ production e.g. by making APP a better substrate for BASE1/beta secretase
  • Increase production of longer 1-42 rather than 1-40 Aβ species → Aβ1-42 is believed to be pathogenic
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16
Q

What do mutations in tau cause?

A

FTD with Parkinsonism linked to chromosome 17 (FTDP-17)

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17
Q

Which gene variants contribute the most to genetic risk for developing AD?

A
  • APOE gene
  • Two variants, one from each parents
  • If E2/E2, probably won’t developing AD at all
  • E4/E4 highest risk but not diagnostic or certain
18
Q

What are the neuritic plaques?

A
  • Plaques sitting next to neurons that are dying

- These are the ones most closely associated with symptoms

19
Q

How can amyloid plaques and tau be monitored in vivo?

A

PET scan using radio tracer that has been tagged to a ligand that is v specific for amyloid or tau

20
Q

What are the parts of progressive pathology in AD (shared by other neurodegenerative diseases)?

A

1) Synaptic dysfunction
2) Neuron loss - slow, causes symptoms
3) Reactive (micro)gliosis - in reaction to build up of plaques, tangles and neuronal loss other brain cells react
- Astrocytes (glia) and microglia become activated in response to those pathologies and change shape and cause damage by constantly emitting toxins and damaging neurons further, leading to neurodegeneration

21
Q

Why does microglia and astrocyte activation occur?

A

Microglia react to the protein aggregates and dysfunctional dying neurons as if they are pathogens

22
Q

What part of the brain is involved in end stage AD?

A

The whole brain, atrophy (starts in hippocampus)

23
Q

Describe the progressive neuronal cell loss in AD

A
  • Starts in entorhinal cortex which contains the hippocampus
  • Then moves and spreads to the basal forebrain and eventually the whole brain as there is neuronal to neuronal transmission of hyperphosphorylated tau which then aggregate wherever they go (explains pattern of distribution of neurons and variation)
24
Q

What imaging technique can be used to see brain atrophy?

A

MRI

25
Q

What can PET be used for?

A

Detect deficits in glucose metabolism that occur quite early on

26
Q

Why is it difficult to target the secretase enzymes for treatment of AD?

A

Bc they have many other substrates other than APP

27
Q

What is the effect of Aβ oligomers on synaptic activity?

A

Decrease it

28
Q

Having more of which type of tau increases your risk of disease?

A

4R

29
Q

What is important to remember about tau aggregates?

A

They can be a feature of normal ageing (no symptoms)

  • Aggregation of tau
  • Hyperphosphorylation of tau
  • Altered expression of tau
30
Q

What is the centre piece of the amyloid cascade hypothesis?

A

Aβ (Aβ leads to tau problems as well)

31
Q

What are risk factors for AD?

A

Head injury, stroke, Down’s syndrome, hip damage?, anxious personality?, education protective?

32
Q

When does AD begin?

A

~ 20 years before diagnosis - therefore by the time someone receives a diagnosis, they have already lost a v large number of neurons

33
Q

What is the progression fo amyloid load in AD?

A
  • Amyloid rising is the first thing you would would in someone that is starting to go beyond normal
  • At some point in the disease it plateaus, and doesn’t get more burden after a certain point
34
Q

What is the problem with using high amyloid as a biomarker for AD?

A

Many brains have high amyloid but are cognitively normal (more complicated than just amyloid, also if remove amyloid no improvement with symptoms)

35
Q

What do AChE inhibitors do?

A
  • They boost the synaptic activity of cholinergic neurons that are still left (the are lost first and most in AD)
  • ACh levels are reduced in AD
  • Not changing the disease so only offer at best mild symptom relief at the v early stages of disease
  • Donepezil, rivastigmine, galantamine prevent breakdown of ACh
  • Galantamine also enhances post-synaptic stimulation
36
Q

What are cholinergic neurons essential for?

A

Memory

37
Q

Which gender is more affected by AD?

A

Women

38
Q

Is late onset normal AD heritable?

A

Yes, but complex genetics

39
Q

Which 3 drugs are used to treat mild/moderate AD?

A

Donepezil, rivastigmine and galantamine

40
Q

What is another type of drug used to treat AD?

A

NMDA receptor antagonists

41
Q

Describe NMDA receptor antagonists?

A
  • AD cellular damage results in increased glutamate release
  • NMDA (fast response) and AMPA (slow response) glutamate receptors are then activated which leads to elevated calcium levels and excitotoxicity
  • Therefore non-competitive NMDA receptor antagonist is licensed for moderate-severe AD (minor effect on disease, not cure)
42
Q

What is the NMDA receptor antagonist used to treat moderate-severe AD?

A

Memantine

Stage 2: Ageing (10 decks)

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