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354: Pathobiology > 1. Alzheimer's Disease > Flashcards

1. Alzheimer's Disease Flashcards

1
Q

what is the most common form of dementia

A

alzheimers disease

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2
Q

name 3 other types of dementia

A

vascular dementia
parkinsons dementia
frontotemporal dementia

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3
Q

who discovered AD

A

Alois Alzheimer

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4
Q

what was the name of Alois Alzheimer’s patient

A

Auguste D

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5
Q

what behaviours did Auguste D exhibit

A

changes in her behaviour: strong feelings of jealousy
memory impairment
speech and language difficulty
paranoia

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6
Q

what did pathological examination of Auguste D’s brain find

A

decreased brain volume
cortex was covered in localised deposits, and some neurons contained dense bundles of filament

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7
Q

name the 3 A’s for clinical symptoms of AD

A

agnosia
apraxia
and aphasia

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8
Q

what is agnosia

A

poor object recognition

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9
Q

what is apraxia

A

inability to make voluntary movements

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10
Q

what is aphasia

A

loss of speech and poor word recognition

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11
Q

what is the main symptom of AD

A

progressive loss of STM

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12
Q

what behavioural changes often accompany these physical symptoms

A

heightened aggression, agitation and sleep disturbances

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13
Q

what proportion of people aged over 80 does AD affect

A

1/6 people

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14
Q

what is the strongest risk factor for AD

A

age

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15
Q

is there a gender bias in AD

A

yes - prevalence and incidence is higher in women than men in Europe and Asia

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16
Q

what percentage of AD cases is due to genetic mutations

A

1.5% of total cases

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17
Q

what is the name given to AD when its due to genetic mutation, why?

A

familial AD - because these mutations occur within families

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18
Q

SNP at over how many genes is associated with an increased risk of developing AD

A

30 genes

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19
Q

which APOE genes is associated with sporadic AD

A

APOE2, APOE3, APOE4

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20
Q

why are APOE genes associated with sporadic AD and not familial AD

A

because these are polymorphisms at APOE and NOT mutations

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21
Q

if you have either 1 or 2 copies of APOE4 how many times more likely are you to develop AD at an early age

A

7-11 x more likely

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22
Q

what 3 modifiable factors predispose the individual to AD

A

metabolic and vascular factors
diet and nutrition
lifestyle

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23
Q

name 2 vascular factors that are risk factors for AD

A

diabetes
hypertension

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24
Q

what diet is associated with an increased risk of AD

A

high in saturated fats
low in vitamin B6 and B12

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25
Q

what can decrease the risk of developing AD

A

engaging in mentally stimulating activities or having a demanding job

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26
Q

name two histopathological features of AD

A

senile plaques (with a halo and a core)
neurofibrillary tangles

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27
Q

are senile plaques intracellular or extracellular

A

extracellular

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28
Q

are NFTs intracellular or extracellular

A

intracellular

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29
Q

where are activated microglia typically found in AD

A

aggregating around extracellular plaques

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30
Q

what other molecule (besides microglia) respond to cell damage

A

reactive astrocytes

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31
Q

what must be found for a pathological diagnosis

A

plaques AND tangles

(plaques are necessary but not sufficient)

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32
Q

what is the main component of senile plaques

A

beta-amyloid protein

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33
Q

what is the main component of NFT

A

tau protein

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34
Q

what stains identify beta-amyloid

A

congo red and thioflavin

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35
Q

where do dyes bind to beta-amyloid

A

on the beta sheets

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36
Q

what makes beta-amyloid resistant to proteolysis

A

they cannot be broken down due to strong beta-sheet structure

37
Q

what is APP

A

a transmembrane protein ubiquitously expressed in neurons

38
Q

what molecule cleaves APP into two fragments in the non-amyloidogenic pathway

A

alpha-secretase

39
Q

in the non-amyloidogenic pathway, what two fragments is APP cleaved into?

A

soluble APP alpha
C83 (protein portion)

40
Q

where does alpha-secretase cleave APP, what does this mean?

A

in the middle of the fragment
- this means that a full sequence of amyloid is not found in either APP fragment

41
Q

what cleaves C83

A

gamma-secretase

42
Q

gamma secretase cleaves C83 into

A

p3

43
Q

what is p3

A

a small fragment less than 38 AA - it is not prone to any aggregation, it is excreted into the extracellular space and is removed by the brain

44
Q

in the amyloidogenic pathway, what cleaves APP

A

beta-secretase

45
Q

what does beta-secrete cleave APP into

A

soluble APP beta and C99

46
Q

what is different about APP cleavage in the non-amyloidogenic pathway

A

it is not cleaved in the middle, so C99 contains the full-length fragment of beta-amyloid

47
Q

what happens when gamma-secretase cleaves C99

A

a small fragment 40-42 AA in length is generated. this is called beta-amyloid 1-40/42

48
Q

what is dangerous about beta-amyloid 1-40/42

A

it is prone to aggregation which results in the loss of neuronal function

49
Q

what is the least toxic amyloid species

A

fibrils

50
Q

what is the most toxic amyloid species

A

oligomers

51
Q

AB40-24 are secreted as monomers, what makes them aggregate?

A

they have high kinetic energy

52
Q

how long are amyloid fibrils

A

8-10 nm

53
Q

how many APP mutations have been identified to date

A

50

54
Q

what do PS1 and PS2 mutations relate to

A

the gamma secretase enzyme - these mutations give it greater cleavage properties

55
Q

what are APP mutations hypothesised to do

A

leave the protein more likely to be cleaved by beta-secretase

56
Q

what are neurofibrillary tangles composed of

A

two PHFs wound around each other

57
Q

what are PHFs composed of

A

hyperphosphorylated tau

58
Q

what happens when tau becomes hyperphosphorylated

A

it falls off the microtubule and aggregates together, destabilising the microtubule and neuronal communication = neuronal death.

59
Q

how many isoforms does tau have

A

6

60
Q

how are tau isoforms generated

A

via alternate splicing of mRNA

61
Q

how many of the tau isoforms do PHFs contain

A

all 6 of them

62
Q

what do MAPT mutations give rise to

A

frontotemporal dementia

NOT AD

63
Q

what do pathogenic mutations do to tau

A

alter microtubule assembly or aggregation. properties

64
Q

what is gliosis

A

the activation of microglia and astorcytes

65
Q

what activates microglia and astrocytes

A

surveying microglia detect these abnormal protein deposits

66
Q

microglia and astrocytes produce pro inflammatory cytokines, name 3 of them

A

1l-1beta

TNF-alpha

IL-6

67
Q

what is the effect of these pro-inflammatory cytokines

A

they produce more neuronal damage = feed-forward mechanism as damaged neurons produce beta-amyloid and tau aggregates

68
Q

what causes cerebral amyloid angiopathy

A

deposition of beta-amyloid in the walls of blood vessels (damages the BBB)

69
Q

what evidence is there for the amyloid cascade hypothesis

A

animals that overexpress human APP mutations develop cognitive impairment and reduced spatial memory

treating animals with compounds that prevent or remove beta-amyloid show improvement in cognitive performance

70
Q

what is the amyloid cascade hypothesis

A

aggregation of beta-amyloid sets off a series of downstream events, including inflammation, that results in the development of NFTs and cell death

71
Q

what is the tau hyppthesis

A

proposes that tau pathology precedes beta-amyloid plaques and that NFTs are the main cause of neuronal death

72
Q

what supporting evidence is there fore the tau hypothesis

A

animals that express human tau NFTs develop cognitive impairment and neuronal death

dementia is also observed in other tauopathies

treating animal models with compounds that prevent tau aggregation show improved cognitive performance

73
Q

name another tauopathy characterised by dementia

A

progressive supranuclear palsy

74
Q

what is the cholinergic hypothesis

A

acetylcholine is important for memory and attention - as cholinergic neurons die early in AD, preventing the catalysis of ACH could improve symptoms

75
Q

name 2 drugs based on the cholinergic hypothesis

A

donepezil
galantamine

76
Q

what is a nasty side effect of donepezil

A

vommiting

77
Q

do PSYC317 questions for more info on AD drugs!!!!

A

yes do it bitch

78
Q

how does memantine work

A

a non-competitive NMDA antagonist that competes with magnesium for binding int he channel - keeping it closed and preventing a calcium influx

79
Q

how many AD clinical trials have failed

A

99.7%

80
Q

name 3 types of drugs in the pipeline for AD treatment

A

immunotherapy - AB42 injections to stimulate an antibody response

beta-secretase inhibitors

gamma-secretase inhibitors

81
Q

describe how immunotherapy is a tool for combatting AD

A

patients injected with pre-aggregated AB42 = antibodies

antibodies cross the BBB and attack senile plaques = disaggregation and phagocytosis

82
Q

has immunotherapy been approved in the UK

A

no - only in the US (aducanumab)

83
Q

what happened in the first trials of immunotherapy

A

they had to be stopped in phase 2 due to brain inflammation and death

84
Q

what has prevented beta-secretase inhibitor development

A

they have been difficult to manufacture as a large binding site is needed for BBB penetration

85
Q

what undesirable side effects are currently associated with beta-secretase inhibitors

A

worsening of cognitive decline

86
Q

what was the problem with the first gamma-secretase inhibitors

A

they initially inhibited notch processing - which is important in the development of many cancers

87
Q

why have these gamma secretase inhibitors been dropped

A

lack of potency, low brain penetration, poor selectivity, lack of efficacy

88
Q

name 3 other approaches to treating AD

A

epigenetic - modify gene expression
inflammation - reduce gliosis
vascular - improve blood flow

89
Q

what does memantine do

A

prevents overexposure to calcium and the production of free radicals which can cause cell death

354: Pathobiology (10 decks)

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