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MBD > Neurodegenerative Diseases > Flashcards

Neurodegenerative Diseases Flashcards

1
Q

What is neurodegeneration?

A

The progressive loss of neurons

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2
Q

What part of the nervous system do neurodegenerative diseases affect?

A

CNS, PNS or both

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3
Q

When do neurodegenerative diseases begin?

A

At any time

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4
Q

What does an earlier age of onset mean?

A

Greater genetic contribution

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5
Q

What does a later age of onset mean?

A

More likely sporadic disease (or idiopathic disease)

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6
Q

Describe why neurodegenerative diseases tend to be very heterogeneous

A
  • Some disease names are actually umbrella terms of conditions
  • Diseases may have overlapping phenotypes but with different causes (like different mutations)
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7
Q

What is the common pattern of most neurodegenerative diseases?

A
  • Molecular impairment in the cell
  • Decreased transmission at synapse
  • Dying back of neurites
  • Cell death
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8
Q

What do neurodegenerative diseases frequently involve?

A
  • Protein aggregation
  • Lysosomal dysfunction
  • Mitochondrial dysfunction
  • Associated inflammation via activation of glia
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9
Q

What are some of the clinical/ research issues in neurodegenerative diseases?

A
  • Rarely manifest obvious symptoms until pathology is severe
  • Study of affected tissue is tricky until after death
  • Remains incurable
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10
Q

What is the most common neurodegenerative disease?

A

Alzheimers

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11
Q

When is normal onset of alzheimers?

A

>65 yrs

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12
Q

What proportion of alzheimers are early onset and when is this?

A
  • 10%
  • Age 30s onwards
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13
Q

What proportion of people have alzheimers aged 85+?

A

50%

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14
Q

What characterises dementia?

A

Decline in memory and other cognitive functions that impair quality of life

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15
Q

What is ‘normal ageing’?

A

Gradual decline in normal cognition, gradual changes in personality

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16
Q

How are the impairments in dementia distinct from normal cognitive lapses?

A
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17
Q

What are some pathological hallmarks of dementia?

A
  • Brain shrinkage
  • Proteinopathies
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18
Q

What types of proteinopathies are present in dementia?

A
  • Amyloid plaques
  • Neurofibrillary tangles
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19
Q

What are amyloid plaques enriched in?

A

Aβ peptides

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20
Q

What is another name for neurofibrillary tangles?

A

Paired helical filaments

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21
Q

What is Aβ? In the context of Alzheimer’s

A

This is a peptide produced by the cleavage of a transmembrane protein called APP (amyloid beta precursor protein) by proteases

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22
Q

What are neurofibrillary tangles?

A

Intracellular protein aggregates that are enriched in Tau protein

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23
Q

What is the amyloid hypothesis?

A

The production of Aβ and amyloid plaques is the major cause of Alzheimer’s

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24
Q

Name the 3 genes that cause early onset Alzheimer’s

A
  • APP
  • PSEN1
  • PSEN2

These are all involved in the processing of APP to Aβ

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25
Q

What are PSEN1 and 2 both components of?

A

Gamma secretase

26
Q

What does tau normally do?

A

Binds microtubules in axons

27
Q

What does displacement of hyperphosphorylated tau cause?

A
  • Aggregates to form tangles
  • Molecules are destabalised
28
Q

What are the three main roles of microtubules in post-mitotic cells?

A
  • Structure/ shape of a cell
  • Positioning of organelles
  • Motorways for transporting vesicular contents
29
Q

Why is the tau hypothesis plausible?

A

This suggests that Tau is upstream of Aβ, so Tau is the main cause

  • evidence is as in late onset (normal, not genetic forms of) AD, Tau is present before amyloid plaques are
30
Q

What does the tau hypothesis suggest?

A

Tau is upstream of A beta

31
Q

Discuss the evidence for the amyloid vs the Tau hypothesis

A
  • Controversial
  • probably is more evidence for amyloid, but therapies based on inhibiting Aβ aggregation so far have not worked!
  • tangles and plaques may both be not pathogenic, and may be by-standers or may even be protective, there is evidence that the big aggregates are not pathogenic, but instead the smaller oligomers
32
Q

What are some other risk factors for alzheimers?

A
  • Down syndrome
  • Gender (women)
  • High BP, CVD and diabetes
  • Low education
  • Head injury
  • Smoking and drinking
  • Small genetic risk contribution
33
Q

What is the second most common neurodegenerative disease?

A

Parkinsons, a ‘movement disorder’

34
Q

What is the average age of parkinsons disease onset?

A

60-65 yrs

35
Q

What are the 4 cardinal features of parkinsons?

A
  • resting tremor (hands shake when not moving then goes when they move the hands)
  • bradykinesia (slow movement)
  • rigidity
  • postural instability (falling over, comes last)
36
Q

How do these features in PD progress?

A

The resting tremor starts in one hand then spreads over to the other hand then the feet and then other parts of the body, also the last feature of Parkinson’s to come is postural instability - patients fall over and may break bones

  • younger patients get resting tremor first
  • older patients may start off with the bradykinesia and rigidity
37
Q

What are the non-motor symptoms of parkinsons?

A
  • Depression and anxiety
  • Loss of smell
  • Sleep disorders
  • Constipation
  • Dementia
38
Q

What are some of the pathological hallmarks of parkinsons?

A
  • Loss of dopaminergic neurons of the substantia nigra
  • Proteinopathies (Lewy bodies)
39
Q

What are lewy bodies?

A
  • Intracellular protein aggregates enriched in alpha-synuclein protein
40
Q

Are lewy bodies pathogenic?

A

No

41
Q

10% of PD cases have a clear genetic cause, name the 3 rough categories

A
  • Early onset autosomal recessive mitochondrial conditions
  • Late onset autosomal dominant
  • Mutations that cause ‘parkinsons plus’ conditions
42
Q

What causes Early onset autosomal recessive mitochondrial conditions?

A

Loss of function mutations in PINK1 and parkin cause decreased mitophagy

43
Q

What is mitophagy?

A

the selective degradation of mitochondria by autophagy

44
Q

Name 4 genetic causes found for late-onset PD

A
  • SNCA (α-synuclein) gene amplification (mutation or duplication), this confirms that α-synuclein is pathogenic
  • LRRK2 gain of function
  • VPS35 gain of function
  • GBA loss of function
45
Q

Explain the function of the GBA gene - what does it encode?

A

GBA encodes GCase - a lysosomal enzyme

46
Q

How do a loss of function mutation in the GBA gene increases your risk of PD?

A
  • α-synuclein degradation in the lysosome one of the last steps in autophagy of mitochondria (mitophagy)
  • GBA encodes GCase which is a lysosomal enzyme that helps to degrade α-synuclein in the lysosome, so loss of function of GCase causes a buildup of α-synuclein!
47
Q

What happens if If there is no GBA mutation but still an increase in a-synuclein?

A
  • The excecss inhibits translocation of GCase into the lysosome for degradation of α-synuclein
  • Results in pathogenic feed forward loop
48
Q

Where is alpha synuclein degraded?

A

In the lysosome

49
Q

How much of parkinsons is genetic?

A

30%

50
Q

What are the risk factors for parkinsons?

A
  • Gender (men)
  • Red hair
  • Head injury
  • Not smoking/consuming caffeine
  • Herbicides, pesticides, insecticides
  • Exposure to metals
  • General anaesthesia
51
Q

Why is the finding of MAPT gene discovered on a GWAS of sporadic PD interesting?

A
  • MAPT codes for Tau which is one of the 2 proteins involved in Alzheimer’s!
  • Neurofibrillary tangles are found in PD brains and even in the same as Lewy bodies but not any great extent - however, more tangles are found in brains of people with LRRK2 mutation PD! This means that microtubule disruption may be implicated in PD
  • So Tau mutation may not be enough for PD but increase risk
52
Q

What is neuroinflammation?

A
  • Activation of the immune system within the nervous system
  • mainly microglia (but also astrocytes)
53
Q

What are the features of reactive microglia?

A
  • Amoeboid shape
  • More motile
  • Production of cytokines
  • Eventually phagocytic
54
Q

What is neuroinflamation caused by?

A
  • neurotoxic insult
  • external triggers e.g Ab can trigger a reactive microglia.
55
Q

What can reactive microglia cause?

A

Protection or damage of neurons

56
Q

How are reactive microglia protective of neurons?

A

Anti-inflammatory cytokine release -> contributes to normal removal of unhealthy cells

57
Q

How can reactive microglia be damaging to neurons?

A

Proinflammatory cytokine release in response to pathogens

58
Q

Explain the effects of ageing on neuroinflammation

A

Ageing induces a shift towards a production of the damaging forms of microglia due to changes in gene expression, so stimuli that should be activating protective functions actually stimulate damaging microglia

  • we call this neuroinflammaging
59
Q

What can microglia be activated by?

A

External triggers (Abeta, environmental toxins and pathogens)

60
Q

Describe how PD may be due to external triggers - this is a new theory

A
  • In PD, we are now understanding that neuroinflammation may be a driving factor
  • We now think that Lewy body pathology in the gut may lead to PD in the brain - so gut inflammation may cause Lewy bodies which can potentially spread via the VAGUS nerve to the brain
  • so gut microbiota may have a role in PD, may also be why PD can cause constipation
61
Q

What are some effects of ageing on neurodegeneration?

A
  • Shortening of telomeres in adults - means that it is harder to replace dying neurones
  • Increased ROS (reactive oxygen species)
  • Changes in gene expression (altered Wnt signalling)

MBD (23 decks)

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