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Molecular Biology of Disease > Alzheimers Disease > Flashcards

Alzheimers Disease Flashcards

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1
Q

What is dementia?

A

A progressive and persistent clinical syndrome defined by a failure of higher neurological functions in a conscious patient.
Umbrella term for many conditions with many causes.

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2
Q

What are examples of higher neurological functions?

A
  • Language
  • Attention
  • Memory
  • Visual spatial perception
  • Abstract thinking
  • Orientation (time and space)
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3
Q

How would a clinician assess someone with dementia?

A
  • Look at changes in higher cognitive functions.
  • Determine if they are temporary or progressive (may take several visits).
  • Diagnose patient with dementia.
  • Work out cause of dementia.
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4
Q

What are the classes of human neurodegenerative disorders?

A
  • Dementia e.g. Alzheimer’s.
  • Movement disorders e.g. Parkinson’s.
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5
Q

Is there overlap between neurodegenerative disorders?

A

Yes - one can lead to another (of a different class).

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6
Q

What is the biggest risk factor for dementia?

A

Age (although it can present in children).

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7
Q

What are the financial costs of dementia?

A
  • Burden on the health and social care systems.
  • Burden on carers (loss of earnings) due to insufficient social care provisions.
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8
Q

How are different types of dementias defined?

A

Differences in which proteins have abnormal folding (confer pathology). Called different proteinopathies.

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9
Q

How do proteinopathies start?

A
  • Abnormal cleavage (a few types of neurodegenerative disease) e.g. in Alzheimer’s
  • Misfolding (most types of neurodegenerative disease) e.g. in prion protein - CJD
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10
Q

How does protein misfolding lead to dementia?

A

The proteasome is unable to degrade the ubiquitinated protein so it aggregates.

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11
Q

Why is the proteasome not able to digest some misfolded proteins?

A

They have an excess of beta sheets (known as amyloid proteins).

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12
Q

What is the most common cause of dementia in the UK?

A

Alzheimer’s disease (AD)

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13
Q

Is AD heritable?

A

Yes but not usually - 99% of cases are sporadic, and 1% familial (autosomal dominant).

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14
Q

Why is there an increased risk of AD in Down’s syndrome patients?

A

A mutation linked with Alzheimer’s (APP) is on chromosome 21 - Down’s people more likely to get it due to extra chromosome.

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15
Q

Is one sex more affected by AD?

A

Yes - females. Maybe because they live longer? Not proven.

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16
Q

What is the age of onset of AD?

A
  • 65-70 in sporadic cases
  • before 60 in familial cases
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17
Q

How long do people with AD usually live after diagnosis?

A

8-10 years.

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18
Q

What do patient’s with AD usually die of?

A

Infection or inanition (not eating).

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19
Q

Is there a diagnostic test for AD?

A

No.

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20
Q

What changes in the brain do we see in patients with AD?

A

Loss of grey and white matter including:
- Larger ventricles
- Atrophied insular cortex
- Atrophied gyrus
- Atrophied hippocampus
- Abnormal beta amyloid plaques on cortical surface and blood vessel walls.
- Sometimes CAA
- Abnormal (hyperphosphorylated) Tau protein aggregates (neuritic plaques)
- Neurofibrillary tangles (also abnormal Tau)

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21
Q

What is cerebral amyloid angiopathy (CAA)?

A

In 40% of AD cases we have CAA - beta amyloid blocking brain blood vessels. Increases risk of brain bleed. Can occur with no AD, but most common in AD patients.

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22
Q

What are neurofibrillary tangles?

A

Build up of abnormal (hyperphosphorylated) Tau protein paired helical filaments in neuron cell body cytoplasm.

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23
Q

What is the APP gene?

A

Amyloid precursor protein on chromosome 21. A region of it is amyloidogenic (encodes amyloid beta protein, part of bigger APP protein) and mutations close to and within this region cause AD.

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24
Q

Which APP processing pathway is non-amyloidogenic (good)?

A

The alpha synthetase pathway - this enzyme complex cuts the APP protein amyloid region in half.

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25
Q

Which APP processing pathway is amyloidogenic (bad)?

A

The beta synthetase pathway - this enzyme complex cuts the APP protein before the amyloid region; amyloid produced after further processing.

26
Q

Which secretase pathway becomes more prominent under stress?

A

Beta.

27
Q

How is beta amyloid usually removed from the brain?

A

(After build up in response to acute brain injury in patients without AD) Beta amyloid is drained through a perivascular (blood vessel surrounding) drainage system called the glymphatic system.

28
Q

Why does beta amyloid build up in the brains of people with AD?

A

The glymphatic system becomes overwhelmed by beta amyloid and blocked, causing beta amyloid plaques form around capillaries.

29
Q

Which stage of AD should new therapies aim to target?

A

Mild cognitive impairment (10-15 years before symptom onset). Intervention could stop AD progression.
By symptom onset it is too late to regenerate neurons.

30
Q

How might we detect early stages of AD?

A
  • Good biomarkers (active area of research)
  • PET scans show build up of amyloid or Tau, but heat map resolution is poor; can’t distinguish early from late cases (also active area of research).
31
Q

What prevention measures are already in place for AD?

A

Brain health clinics; people in 40s-50s can be interviewed and advised on lifestyle management, have PET scans, be given access to clinical trials etc.

32
Q

What is the MAPT gene?

A

Microtubule associated protein Tau on chromosome 17. Several isoforms of MAPT (4 repeat and 3 repeat). Involved in MT stabilisation and spacing (sits on MT surface). Mutations in this gene cause a neurodegenerative disease similar to Parkinson’s.

33
Q

What happens when Tau is hyperphosphorylated by kinases?

A

It forms paired helical filaments with itself and the MT starts to disassemble.

34
Q

What triggers the beta amyloid pathway prominence or Tau to become hyperphosphorylated?

A

We don’t know.

35
Q

What is the result of neurofibrillary tangles?

A

Tau builds up in cytoplasm and kills the neurons.

36
Q

Is AD a neuroinflammatory condition?

A

No - although it is often incorrectly referred to as one. Lymphocytes are not recruited from the periphery. Microglial cells are relesing cytokines, but not any more than they normally do.

37
Q

Which 3 genes account for the vast majority of familial AD (fAD)?

A
  • APP (chr 21)
  • PSEN1 (chr 14)
  • PSEN 2 (chr 1)
38
Q

Which gene is behind the most cases of fAD?

A

PSEN1 (180 described mutations compared to 30 for APP and 14 for PSEN2).

39
Q

What is the result of an appropriate fAD mutation?

A
  • AD guarantee
  • Earlier AD onset (sometimes 20s but usually 40s/50s).
40
Q

Which gene increases susceptibility to sporadic AD?

A

The APOE4 polymorphism of APOE (homozygous). (APOE2 is protective).

41
Q

What is the result of a homozygous APOE4 polymorphism?

A

AD not guaranteed, but much more likely.

42
Q

What are APP mutations named after?

A

Locations of families they were initially found in.

43
Q

What does PSEN1 KO do?

A

Substantially reduces the formation of amyloid beta.

44
Q

What are PSEN1 and 2 proteins catalytic subunits of?

A

The gamma secretase complex; help cleavage of APP.

45
Q

Do the PSEN1/2 mutations increase AD risk by impacting the APP cleavage?

A

No - APP KOs with PSEN1/2 mutations still showed increased neurodegeneration features. Affects pathways independent of beta amyloid.

46
Q

Which regions of the PSEN1 protein are commonly mutated to cause fAD?

A

Transmembrane domains.

47
Q

What is the APOE protein involved in?

A

Moving lipids around the brain. E4 polymorphism means function is reduced. E2 polymorphisms means function is maximal.

48
Q

What does APOE genotype impact?

A

Age of onset of AD (and therefore proportion of genotype affected by AD) in sporadic and familial cases. E4 = early onset.

49
Q

How does the APOE protein contribute to AD phenotype?

A
  • Present in mayloid beta plaques.
  • May interact with neurofibrillary tangles.
50
Q

What are non-modifiable risk factors for AD?

A
  • Age
  • Female sex
  • APOE4 genotype
51
Q

What is the theme relating modifiable risk factors for AD?

A

They are mostly cardiovascular. Reduce risk through improving diet, exercising, stopping smoking.

52
Q

What is the most effective AD prevention tactic?

A

Education and lifestyle improvement.

53
Q

Why have no AD drugs been successful?

A

Rodent models are not very suitable (don’t naturally get AD) but are commonly used in studies - fAD mutations are induced artifically expressed APP.
Most APP mutation models do not replicate AD pathology (Tau and beta amyloid plaques).
Most promising results with overexpression of mutated APP and Tau.

54
Q

Why do in vitro and ex vivo testing often get skipped in AD therapy development?

A

Therapies go straight to clinical trial because there are none available yet so there is lots of money to be made. None have worked yet though!

55
Q

Which Tau related therapies have been tried and failed?

A
  • Kinase inhibitors to stop hyperphosphorylation of Tau.
  • Activation of phosphatases to dephosphorylate the Tau.
  • Introduction of MT stabilizing agents.
56
Q

Which Tau related therapies are looking promising?

A

Immunotherapy: uses antibodies to remove the abnormal Tau from the body, like they are pathogens.
Still only at a very early stage in clinical trial though.

57
Q

Which beta amyloid related therapies have been tried and failed?

A
  • Inhibitors of the beta secretase pathway.
  • Inhibitors and modifiers of the gamma secretase pathway.
  • Activators of the alpha secretase pathway.
  • Immunotherapies (although these are approved) - Abs bind beta amyloid and aid in its drainage. Successful at removing it from brain but patient still has dementia. Also don’t slow onset from mild cognitive impairment to AD.
58
Q

What should new AD therapies focus on?

A

The root cause - small vessel disease (a type of cerebrovascular disease) (everyone with sporadic AD has it).
Reduced oxygen to the neurons (high metabolic needs) pushes them towards the beta secretase pathway and could be a significant factor in the onset of AD (e.g. might be linked to Tau hyperphosphorylation).
Makes sense why AD occurs with age because as we age there is reduced cerebral perfusion (blood flow to the brain).

59
Q

Why is it hard to distinguish between AD and vascular dementia (VD)?

A

They have similar phenotypes e.g. small vessel disease.
Strokes can help with diagnosis (more common in VD).

60
Q

Who should be specifically targeted for dementia prevention?

A

People at risk of cerebrovascular disease and therefore at risk of AD. They can improve risk through lifestyle.

61
Q

Is there a link between severe head injury and AD?

A

Yes - the head injury damages the neurons so (if the person lives long enough) they are more likely to get AD.

62
Q

Is there a link between repetitive mild head injury and AD?

A

There is not sufficient evidence to conclude a link. The benefit of playing a contact sport outweighs the risk of developing AD.

Molecular Biology of Disease (5 decks)

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