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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
Which enzymes carry out 5% of APP metabolism?
B-secretases and y-secretases
25
Does APP metabolism with B- and y-secretases produce toxic breakdown products?
yes: B- and y-secretases cleave around the BA4 component of APP and therefore produce toxic aB peptides
26
Is APP metabolism with B- and y-secretases common?
No - this type of metabolism is found in very rare AD families
27
Give five examples of mutations causing AD
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
what mutation is responsible for 60% of familial AD?
mutations in presenilin 1 (on chromosome 14) and presenilin 2 (on chromosome 1)
29
What are presenilins?
a family of TM proteins that act as the enzymatic component of the y-secretase intramembrane protease complex
30
What other proteins, a part from presenilin, make up the y-secretase intramembrane protease complex? What are their roles?
APH-1, nicastrin, DIYGS and PEN-2 - these are structural proteins
31
How does the y-secretase intramembrane protease complex cleave APP?
the complex forms a water-filled pore around APP and cleaves it via an aspartyl active site to produce aB
32
What is the natural function of the y-secretase intramembrane protease complex?
it cleaves type I membrane proteins
33
What are the potential side effects of inhibiting presenilin/y-secretase to treat AD?
notch signalling/the notch phenotype, tumour formation and neurodegeneration
34
What is a common y-secretase inhibitor?
Ibuprofen
35
What is B-secretase?
A type I TM protein coded by the BACE-1 gene on chromosome 11
36
What FAD mutation involves BACE-1/B-secretase?
the Swedish APP mutation makes APP a better substrate for B-secretase
37
What is APOE?
apolipoprotein E, a plasma cholesterol transporter produced by astrocytes and coded by the APOE gene on chromosome 19
38
What is APOE required for?
neuronal repair
39
What are three APOE alleles? Which one is linked to AD?
E2, E3 and E4 alleles - E4 is linked to an increased risk of developing AD as it accelerates aB aggregation
40
Give six examples of enzymes that degrade amyloid B
insulin degrading enzyme (IDE), APOE/LRP, A2M/LRP, neprilysin, ECE-1 and MMP-9
41
What is the insulin degrading enzyme? How is it linked to AD?
IDE is the major brain enzyme responsible form aB degradation
42
How does APOE usually degrade aB?
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
How does A2 macroglobulin (A2M) naturally degrade aB?
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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