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

Alzheimer's Disease Flashcards

0
Q

What are the two core pathological features of AD?

A

senile plaques and neurofibrillary tangles

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1
Q

How is Alzheimer’s disease described?

A

A progressive loss of cognition, memory and personality

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2
Q

What are the pathological features of general dementia?

A

shrinkage of the temporal and frontal lobes

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3
Q

What are additional pathological features of AD?

A
  • early loss of the hippocampus
  • neuronal loss and synaptic degradation
  • glial cell activation
  • vascular pathology
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4
Q

What are senile plaques?

A

extracellular deposits of aggregated amyloid beta peptide

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5
Q

How do senile plaques physically contribute to AD pathology?

A

plaques physically obstruct communication between neurones

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6
Q

How to senile plaques secreting amyloid B peptide contribute to AD pathology?

A

How do senile plaques secreting amyloid B peptide contribute to AD pathology?

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7
Q

What is amyloid B?

A

A 40-42 amino acid peptide cleaved from the amyloid precursor protein (APP)

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8
Q

Which chromosome can the amyloid precursor protein be found on?

A

chromosome 21

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9
Q

How is AD linked to Down’s Syndrome

A

individuals have three copies of the APP gene (three copies of chromosome 21) and therefore develop early AD pathology and dementia

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10
Q

What is the amyloid precursor protein?

A

an integral type I transmembrane protein highly expressed throughout the body

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11
Q

Name three elements of the amyloid precursor protein

A

Kunitz protease inhibitor domain, OX2 and BA4

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12
Q

What is BA4?

A

The pathological/toxic fragment of APP

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13
Q

Why is BA4 toxic in AD?

A

BA4 is the hydrophobic portion of APP and therefore has a natural propensity to aggregate and form senile plaques

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14
Q

What is the natural function of the amyloid precursor protein?

A

1 - involved in the formation of synapses

2 - protease nexin II (form of APP) involved in blood clotting regulation

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15
Q

What are ADDLs?

A

amyloid-B derived diffusible ligands: small, soluble aggregates (3-4 molecules) of aB peptide

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16
Q

What is the significance of ADDLs in AD?

A

Tg AD mice show memory deficits alongside increased ADDL levels before any AD pathology is seen, suggesting that ADDLs may be the toxic components of AD

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17
Q

Is there a potential for vaccination against AD?

A

Yes - Tg AD mice vaccinated with aB produced antibodies against aB, pushing the equilibrium towards the aB end of the cascade and decreasing the production of ADDLs and senile plaques

18
Q

Which three enzymes can APP be metabolised by?

A

a-secretase, B-secretase and y-secretase

19
Q

Which enzyme carries out 95% of APP metabolism?

A

a-secretases

20
Q

Does metabolism of APP by a-secretases produce toxic breakdown products?

A

No, as a-secretases cleave within the BA4 segment of APP therefore do not produce any aB

21
Q

Name two of the main a-secretases

A

ADAM 10 and TACE

22
Q

a-secretase activity can be constitutive or… ?

A

regulated by environmental influences on the cell via TGN/surface interactions

23
Q

What treatments have the potential to increase a-secretase activity?

A

muscarinic M1 agonists e.g. talsacladine

24
Q

Which enzymes carry out 5% of APP metabolism?

A

B-secretases and y-secretases

25
Q

Does APP metabolism with B- and y-secretases produce toxic breakdown products?

A

yes: B- and y-secretases cleave around the BA4 component of APP and therefore produce toxic aB peptides

26
Q

Is APP metabolism with B- and y-secretases common?

A

No - this type of metabolism is found in very rare AD families

27
Q

Give five examples of mutations causing AD

A

1 - APP mutations making it a better substrate for B/y-secretase
2 - extra copies of the APP gene
3 - presenilin 1/2 (i.e. y-secretase) mutations
4 - APOE e4 allele
5 - A2M mutation

28
Q

what mutation is responsible for 60% of familial AD?

A

mutations in presenilin 1 (on chromosome 14) and presenilin 2 (on chromosome 1)

29
Q

What are presenilins?

A

a family of TM proteins that act as the enzymatic component of the y-secretase intramembrane protease complex

30
Q

What other proteins, a part from presenilin, make up the y-secretase intramembrane protease complex? What are their roles?

A

APH-1, nicastrin, DIYGS and PEN-2 - these are structural proteins

31
Q

How does the y-secretase intramembrane protease complex cleave APP?

A

the complex forms a water-filled pore around APP and cleaves it via an aspartyl active site to produce aB

32
Q

What is the natural function of the y-secretase intramembrane protease complex?

A

it cleaves type I membrane proteins

33
Q

What are the potential side effects of inhibiting presenilin/y-secretase to treat AD?

A

notch signalling/the notch phenotype, tumour formation and neurodegeneration

34
Q

What is a common y-secretase inhibitor?

A

Ibuprofen

35
Q

What is B-secretase?

A

A type I TM protein coded by the BACE-1 gene on chromosome 11

36
Q

What FAD mutation involves BACE-1/B-secretase?

A

the Swedish APP mutation makes APP a better substrate for B-secretase

37
Q

What is APOE?

A

apolipoprotein E, a plasma cholesterol transporter produced by astrocytes and coded by the APOE gene on chromosome 19

38
Q

What is APOE required for?

A

neuronal repair

39
Q

What are three APOE alleles? Which one is linked to AD?

A

E2, E3 and E4 alleles - E4 is linked to an increased risk of developing AD as it accelerates aB aggregation

40
Q

Give six examples of enzymes that degrade amyloid B

A

insulin degrading enzyme (IDE), APOE/LRP, A2M/LRP, neprilysin, ECE-1 and MMP-9

41
Q

What is the insulin degrading enzyme? How is it linked to AD?

A

IDE is the major brain enzyme responsible form aB degradation

42
Q

How does APOE usually degrade aB?

A

binds to and complexes with aB, the complex moves into the cell through interaction with the low density lipoprotein receptor (LRP) and is degraded in a lysosome

43
Q

How does A2 macroglobulin (A2M) naturally degrade aB?

A

binds to and complexes with aB, the complex moves into the cell through interaction with the low density lipoprotein receptor (LRP) and is degraded in a lysosome

Diseases of the Nervous System (6 decks)

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