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Diseases of the Nervous System > Alzheimer's Disease > Flashcards

Alzheimer's Disease Flashcards

1
Q

What is the frequency in the general population?

A

Over 65 years - 10%

Over 85 years - up to 50%, then flattens out

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2
Q

What are the symptoms of Alzheimer’s disease?

A 
Short term memory loss
Increasing memory loss
Anxiety
Depression
Aggressive behaviour
Incontinence and motor problems in terminal phasen
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3
Q

What are the neurochemical symptoms of AD?

A

Glutamate reduction in association cortex and hippocampus.

Excitatory acetylcholine input to cortex reduced.

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4
Q

What is the neuropathology of AD?

A

Loss of synapses
Amyloid plaques
Neurofibrillary tangles
Neurone death

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5
Q

In what order do tangles form?

A

Transentorhinal cortex
Entorhinal cortex
Hippocampus
Amygdaloid nucleus

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6
Q

Where are amyloid plaques located?

A

Found much more widely than NFTs.

However found in higher density around NFTs.

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7
Q

How do neuronal symptoms correlate with behavioural symptoms?

A

Synaptic loss correlates best.
NFT distribution correlates well.
Amyloid plaque distribution correlates only in part.

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8
Q

How has the mechanism of AD been studied?

A

Biochemical analysis of neuropathological deposits
Human genetic analysis of familial AD.
Cell culture and transgenic animal models to study effects of genes and proteins.

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9
Q

What is the predominant form of amyloid plaques?

A

Aβ42

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10
Q

Which other type of amyloid is also present in plaques and is the predominant form in the normal human brain?

A

Aβ 40

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11
Q

Which form of amyloid more readily form aggregates?

A

Aβ42

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12
Q

Other than amyloid beta peptides, what else is found in plaques?

A

Other proteins and peptides, e.g. alpha-synuclein fragment, ubiquitin, complement components.

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13
Q

What is the precursor of Aβ42?

A

APP (Amyloid precursor protein)

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14
Q

What is the effect of increased levels of Aβ42 and Aβ43?

A

They are directly toxic.
They affect tau phosphorylation.
They lead to amyloid deposits forming at a much faster rate than normal.

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15
Q

Which form of Aβ peptides are toxic?

A 
Soluble forms (dose dependent)
(Large amyloid deposits are not toxic in themselves)
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16
Q

In cell culture what has Aβ42 toxicity been shown to do?

A 
Depress synaptic function.
Act at ER to cause calcium release.
Perturb mitochondrial function.
Induce caspase activation and apoptosis. 
Stimulate tau hyperphosphorylation.
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17
Q

How many enzymes cut APP to make Aβ.

A

3 enzymes call secretases.

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18
Q

How are Aβ peptides different lengths?

A

Due to secretase cleavage site variability.

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19
Q

Where does α secretase cleave?

A

In APP, extracellularly within the Aβ sequence.

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20
Q

Where does β secretase cleave?

A

In APP, extracellularly, further out than the α secretase cleavage site.

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21
Q

Where does γ secretase cleave?

A

Within the transmembrane region of APP at a variable location, which is why Aβs of various lengths are produced.

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22
Q

What kind of processing destroys the Aβ region?

A

αγ

Increasing αγ or just α activity will result in less Aβ42.

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23
Q

What kind of secretase process yields Aβ42?

A

βγ

Increasing βγ will result in more Aβ42.
Inhibiting βγ will result in less Aβ42.

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24
Q

What kind of molecule is α secretase?

A

A member of the ADAM class of zinc metalloproteinases.

ADAM = A Disintegrin And Metalloproteinase

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25
Q

Which types of ADAM can act as α secretase in cell lines?

A

9, 10, 17

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26
Q

What happened when ADAM 10 was overexpressed in mice?

A

Prevented amyloid accumulation.

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27
Q

What are the two important components of γ secretase?

A

PS1 and PS2

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28
Q

What are the structures of PS1 and PS2?

A

Very similar transmembrane proteins with 9 transmembrane domains and intracellular N terminus.

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29
Q

What kind of protease does γ secretase act as?

A

Membrane locate aspartyl protease.

30
Q

What kind of molecule is β secretase?

A

Cysteine protease

BACE - Beta-site APP Cleaving Enzyme

31
Q

What are the 4 components of γ secretase?

A

PS1 and/or PS2
Nicastrin
Aph-1
PEN2

32
Q

Mutations in which genes cause familial Alzheimer’s disease?

A

PS1 (over 150 mutations known)
PS2 (20 mutations known)
APP (20 mutations known)

33
Q

What kind of mutations are in PS1 and PS2?

A

Missense
No nonsense mutations.
This implies gain or alteration of function.
However a deletion of exon 9 causes familial Alzheimer’s.

34
Q

How were the presenilin mutations found?

A

Genetic mapping, isolated cDNAs from this region, did DNA sequence comparisons of AD patients to normal relatives.

35
Q

What could mutations in presenilin cause?

A

Altered binding - more to β secretase and/or less to α secretase.

Changes in exact cleavage site preference to make the more dangerous isoforms - more Aβ42 than Aβ40.

Altered cell localisation to favour β secretase complex formation e.g. BACE is in the trans-golgi and endosomes, ADAM is extracellular so increased localisation to the trans-golgi would yield more Aβ42.

36
Q

Which chromosome is APP on?

A

Chromosome 21

37
Q

How do APP mutations cause familial AD?

A

Increase in overall Aβ levels.
Shifts in Aβ isoform ratios, so that there is relatively more of Aβ42 compared to Aβ40.
Alteration in oligomerisation/aggregation propensity of Aβ peptides.

38
Q

What are the best known APP mutations that cause Alzheimer’s?

A

Swedish double mutation KM 670/671 NL enhances β secretase cleavage site - makees more of all forms of Aβ, including too much Aβ42.

Arctic mutation E693G increases tendency of amyloid peptides to aggregate.

V717I, V717G, V717F affect γ secretase cleavage site selection to favour Aβ42 over Aβ40.

39
Q

What is the link between Down’s Syndrome and Alzheimer’s disease?

A

All people with Down’s syndrome develop Alzheimer’s in their 30s or 40s.

40
Q

What were ADAM10 mutations recently associated with?

A

Reduced α secretase activity found in families with high incidence of late onset Alzheimer’s.

First suggestion that decreased α secretase activity can cause Alzheimer’s disease.

41
Q

What are neurofibrillary tangles composed of?

A

Paired helical filaments.

42
Q

What is the core constituent of paired helical filaments?

A

A 12kD fragment from a tandem repeat region with the tau (MAPT) protein.

43
Q

What is the normal function of tau?

A

To stabilise microtubules.

44
Q

How many isoforms of tau are expressed in the brain?

A

6 - generated by splicing in or out exons 2, 3 and 10

45
Q

An inhibitor of which kinase was tested on mice and found to delay or prevent pathology?

A

ERK2 - extracellular signal-regulated kinase 2

It phosphorylates tau.

46
Q

What are the other components of NFTs?

A

Other cytoskeletal proteins including neurofilament subunits, vimentin, actin MAP2, plus ubiquitin and beta-amyloid.

47
Q

Where is tau phosphorylated?

A

17 different Ser/ThrPro motifs.

48
Q

What is the consequence of abnormal phosphorylation?

A

It prevents normal binding to tubulin, destabilising microtubules, inhibiting axonal transport, resulting in paired helical filaments assembly and disease.

49
Q

What is the second most common early-onset dementia after Alzheimer’s?

A

Fronto-temporal lobar degeneration (FTD or Pick’s disease)

50
Q

Who can Pick’s disease occur in?

A

Patients with amyotrophic lateral sclerosis

51
Q

What is a subset of Pick’s disease?

A

Tau-positive fronto-temporal dementia with parkinsonism (FTDP-17)

52
Q

What causes FTDP-17?

A

Mutations in the MAPT gene of chromosome 17.

53
Q

What do Alzheimer’s disease, Parkinson’s and FTDP-17 all have in common?

A

Increased gene dosage leads to protein aggregates.

54
Q

The allele of which gene is important in determining risk of late onset Alzheimer’s disease?

A

ApoE

55
Q

What is the role of ApoE?

A

It is a lipid transport protein made by glia in the brain.

56
Q

What is Dutch amyloid disease?

A

It is a disease that results in brain blood vessel dysfunction due to extensive amyloid deposition at the endothelium.

57
Q

Which mutations are found to be associated with Dutch amyloid disease?

A

ApoE

58
Q

Where is Aβ42 produced?

A

Lipid rafts - lipid rafts are membrane domains that are rich in cholesterol, sphingolipids, glycosphingolipids and acylated proteins.

59
Q

What affect can decreasing cholesterol have?

A

Decreases Aβ production and increasses SAPP α cholesterol levels, may modulate Alzheimer’s onset probability.

60
Q

What does production of Aβ depend on?

A
  1. The relative activities of αγ and βγ secretase pathways.
  2. The sequence of APP, particularl at and near the α and β and γ secretase cleavage sites.
  3. Levels of APP synthesis.
  4. Presenilin protein sequence.
61
Q

What does the degradation of Aβ depend on?

A
  1. Specific proteases: neurona, extracellular and in glia.
  2. General cell clean-up (ubiquitin/proteasome system, lysosome system)
  3. Clearance through BBB via ApoE and LRP1 in vascular endothelium into blood.
62
Q

What kind of animal models have been made for AD?

A

Various transgenic mouse models.

Transgenic flies with Alzheimer’s from Aβ42 toxicity alone.

63
Q

Describe transgenic mouse models 1.

A

hAPP mutant expression.
Variants:
- mutant used
- promotor used (expression level, location, inducibility)

Mice expressing V717F e.g. PDAPP straing. V717F selectively increases Aβ42 and not other Aβs. Primarily age dependent diffuse amyloid deposits, no amyloid in blood vessels, minor learning deficits, some synaptic loss. No NFT.

Mice expressing KM670/671NL e.g.Tg2576 increases both Aβ42 and Aβ40. Shows age dependent mostly dense core plaque formation (some diffuse) and and blood vessel amyloid, memory deficit. No NFT.

64
Q

Describe the transgenic fly model of AD.

A

Transgenic drosophila were made, expressing Aβ42 (in a cleavable fusion protein) from a pan-neuronal promoter.

Amyloid deposits occurred.

Very extensive cell death (unlike mouse neurons).

No NFTs.

65
Q

Describe the second transgenic mouse model of AD.

A

hAPP mutant plus PS1 mutant expression.

Accumulate amyloid faster, showw memory deficits at earlier age.

Generally get increased levels of dense core plaques relative to diffuse plaques compared to APPV717F alone.

No NFT.

66
Q

Describe the third transgenic mouse model of AD.

A

Double mutant M233t/L235P knock-in at the PS1 gene.

Human APP751 with both the V717I and the swedish K670N/M671L mutations.
All driven pan-neuronally by the Thy1 promoter.

By 10 months there is up to 50% loss of pyramidal neurones in the hippocampal CA1 and 2 regions: cell loss detectable at 6 months.

Aβ is accumulated with Aβ42 as teh main species, but there are not extracellular deposits. No NFT.

Indicates that intracellular Aβ42 is the toxic agent.

67
Q

Describe the fourth transgenic mouse model of AD.

A

Overexpress Aβ42 or Aβ40 alone, without APP overexpression.

Achieved by fusing Aβ to a carrier membrane protein (BRI) with a protease sensitive linker.

Aβ42 expressers have both diffuse amyloid and actual plaques that stain with Congo red.

Aβ40 expressors have NO plaques.

When Aβ42 expression is combined with APP mutation, more extreme plaque formation occurs. But, no cell death or NFT observed.

Indicated Aβ42 is required for plaque initiation.

68
Q

What happens in mice expressing human tau mutant forms?

A

Wide spread cell death occurs.
NFT found.
No amyloid plaques.

69
Q

Describe the fifth transgenic mouse model of AD.

A

Co-expressed hAPP swedish and Tau VLW mutations.
Showed increased phosphorylation of tau.
Cell loss in CA1 of the hippocampus
NFTs very late in life.
Increased amyloid deposition compared to hAPP Swe alone, suggesting that tau may have affects on Aβ biochemistry in some way.

70
Q

Describe the sixth transgenic mouse model of AD.

A

3xTgAD strain.
APPswe
PS1 M416V
MAPT (tau) P301L
Plaques early at 6 months, full MAPT (tau, NFT) pathology by 12 months.
APP mutants enhance MAPT pathology.
Aβ42 definitely accelerates MAPT pathology in mice.
Perhaps Aβ42 is needed to initiate MAPT pathology in human brain.

71
Q

Which treatments are available for Alzheimer’s?

A

Galantamine and Aricept are inhibitors for acetylcholinesterase.
Facilitate cholinergic transmission.
Typically postpone cognitive decline.
Symptomatic relief rather than addressing underlying cause and progression of the disease.

Diseases of the Nervous System (15 decks)

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