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ICB - Neurobiology > Neurobiology 8 > Flashcards

Neurobiology 8 Flashcards

1
Q

Give examples of the features of ageing.

A

Genomic instability.
Shortening of telomeres.
Stem cell exhaustion.

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2
Q

Give a definition of healthy ageing.

A

No specific disease, natural ageing and dying without any debilitating disease. (little or no neuronal loss)

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3
Q

Give a definition of dementia.

A

Progressive loss of cognitive functions, including memory , without impairment of perception or consciousness.

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4
Q

What disease is the most common form of dementia?

A

Alzheimer’s disease

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5
Q

In Alzheimer’s, do circuitry responsible for making neuromodulators degenerate?

A

Yes - lack dopamine means addictive means addictive behaviours are lost (reduced urge to smoke).

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6
Q

What does the brain of Alzheimer’s disease look like?

A

Brain appears shrivelled - substantial loss of brain volume.

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7
Q

Why is there widespread neuronal death in AD brain?

A

Because most neurons are post-mitotic so will not regenerate.

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8
Q

What happens to the remaining (alive) neurons in the brain of an AD patient?

A

They have degenerated myelin and axons - so slower conduction.

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9
Q

What can form amyloid fibrils?

A

Partially folded intermediates/degraded fragments.

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10
Q

Can all types of proteins form amyloids?

A

Yes.

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11
Q

What does the fact that all proteins can form amyloid fibrils suggest?

A

That amyloid fibrils are the real thermodynamic minimum in folding.

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12
Q

What % of people have Alzheimers +65 years?

A

10%

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13
Q

What % of people have Alzheimers +85years?

A

50%

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14
Q

What happens to brain tissue that contain amyloid plaques?

A

They form neurofibrillary tangles.

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15
Q

Where do you find amyloid plaques?

A

Found between neurons - extracellular.

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16
Q

Where do you find neurofibrillary tangles?

A

Found between axons and cell bodies (intracellular).

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17
Q

What do amyloid plaques consist of?

A

Beta-amyloid peptides

Can also contain ApoE cholesterol binding protein

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18
Q

What are neurofibrillary tangles made of?

A

Formed of paired helical filaments - main component is hyperphosphorylated Tau protein.

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19
Q

Which protein is Amyloid Beta peptide derived from?

A

Amyloid beta precursor protein (AbetaPP) - it undergoes proteolysis to form this.

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20
Q

What is the pathway of amyloid fibril formations?

A

Native –> amyloidgenic intermediate –> oligomers –> protofibrils –> amyloid fibrils.

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21
Q

What is the most toxic species in pathway?

A

Oligomers - not structurally defined.

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22
Q

Are amyloid fibrils resistant to detergents/unfolding agents?

A

Yes.

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23
Q

What do oligomers have the ability to do?

A

Penetrate cellular membranes.

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24
Q

What secondary structure are amyloids made of?

A

Extended beta sheets.

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25
Q

What is distance between beta strands in amyloids? and what is distance between beta sheets in amyloids?

A

4.7A and 10.7A

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26
Q

‘Some people develop AD at a younger age (30-40)’ why does this happen?

A

Genetic predisposition - 1%

27
Q

What 3 mutations are associated with a genetic predisposition for early onset AD?

A

Mutations in:

  1. amyloid precursor protein.
  2. PS1 - presenilin 1
  3. PS2 - presenilin 2
28
Q

What is the strongest genetic risk factor for late on set AD?

A

ApoE4 allele.

29
Q

What are the 2 possible SNPs within the ApoE4 result in?

A

3 possible alleles:

E2, E3, E4.

30
Q

What 3 proteases are responsible for cleaving APP?

A

Alpha-secretase, beta secretase and gamma secretase.

31
Q

What part of APP does gamma secretase cleave?

A

The N terminal region.

32
Q

What region does gamma secretase cleave in APP?

A

The C terminal region.

33
Q

Where is presenilin 1 found?

A

It is one of the 4 core proteins in the gamma secretase complex.

34
Q

Give examples of gamma secretase substrates which result in cell signalling.

A

Notch, ErbB4, N-cadherin and E-cadherin.

35
Q

What can the soluble form of beta amyloid cause?

A

Can cause poisoning of LTP - could possibly account for memory loss.

36
Q

What is normal function of amyloids?

A

May have a function in the storage of peptide hormones - peptide and protein hormones stored in amyloid-like beta sheet rich conformation to save space in vesicles.

37
Q

What is the tau protein?

A

Tau is an intrinsically disordered protein.

38
Q

What does tau bind to?

A

Selectively binds to microtubules and also has other domains that bind different molecules - role in signalling.

39
Q

What happens when there are mutations in the tau gene?

A

Microtubules degenerate and tau deposits form.

Formation of neurofibrillary tangles.

40
Q

Does tau tend to be phosphorylated or not?

A

Yes

41
Q

What sort of structure does hyperphosphorylated tau assume?

A

An amyloid like structure.

42
Q

Where are tau filaments found in the brain of an AD patient?

A

Spread from the hippocampus through the cortex.

43
Q

What are the normal functions of tau?

A

Main function: regulates microtubules in axonal transport.

Also involved in the formation of dendritic spines and in maintenance of DNA.

44
Q

What happens if tau cannot regulate microtubules in axonal transport?

A

Neuronal function degenerates.

45
Q

Give examples of some treatments for Alzheimer’s disease?

A 
Secretase inhibitors (beta/gamma) - inhibits Beta amyloid production. 
Phosphorylation inhibitors  - reduce tau hyperphosphorylation.
46
Q

What is the problem with inhibiting secretases and kinases to treat AD?

A

They have other targets within the body so produce bad side effects.

47
Q

What is the second most common neurodegenerative disease?

A

Parkinson’s disease.

48
Q

List some symptoms of Parkinson’s disease.

A

Cannot plan movements or thought.
Tremors.
Dementia (late stage).

49
Q

What causes PD?

A

Lewy bodies formed from aggregation of alpha synuclein.

50
Q

What percentage of cases does familial PD account for?

A

15%

51
Q

What mutations are associated with familial PD?

A

Alpha-synuclein gene (usually early on set).

Leucine rich repeat kinase 2 gene (late onset)

52
Q

What gene is increases the risk of getting PD (does not cause it)?

A

Glucocerebrosidase (GBA) gene.

53
Q

What is juvenile onset PD?

A

A rare form of PD occuring in those under 20.

54
Q

What is juvenile onset PD thought to be caused by?

A

Defects in mitochondrial damage repair.
E3 ubiquitin ligase (Parkin).
Mitochondrial protein kinase (PINK1).

55
Q

Give examples of mutations in the Alpha synuclein gene (SNCA).

A

Increased gene dosage, due to gene duplication/triplication - over-expression of protein.
Missense mutations.

56
Q

Can alpha synuclein be converted to a toxic structure containing beta sheets?

A

Yes.

57
Q

What does shaking a-synuclein at a specific temperature cause?

A

Conversion to the toxic beta sheet form.

58
Q

Why do non-motor symptoms appear first?

A

Deposits of a-synuclein begin in the gut and spread to the brain stem.

59
Q

Where do the aSN deposits spread to from the brain stem?

A

The hypothalamus (involved in sleep)

60
Q

Which neurons does aSN kill?

A

Dopmaine neurons.

61
Q

How could PD be treated?

A

Dopamine neuron transplant - using stem cells.

62
Q

Why is a dopamine neuron transplant not very efficient for PD?

A

The lewy bodies spread into the transplant neurons.

63
Q

What the size of Prion protein and what is it bound to?

A

209aa and membrane bound.

64
Q

Is prion protein self propagating and what does this mean?

A

Yes - can convert normal cellular prion protein to scrapie protein.

ICB - Neurobiology (8 decks)

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