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Applied Neuroanatomy > Alzheimers Disease > Flashcards

Alzheimers Disease Flashcards

1
Q

what is dementia?

A

an irreversible, progressive brain disease that slowly destroys memory and cognitive skills

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2
Q

What may dementia affect?

A

comprehension, calculation, learning, language, judgement and potentially also personality, mood, behaviour and motivation

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3
Q

what is the mean survival following AD diagnosis?

A

7 years

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4
Q

What is the commonality in 80+ year olds?

A

1 in 5

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5
Q

How common is AD in terms of dementias?

A

55%

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6
Q

Where are signs of AD first noticed in the brain?

A

Enterohinal cortex

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7
Q

Where does AD progress to from the enterohinal cortex?

A

hippocampus

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8
Q

What is the enterohinal cortex a part of ?

A

the temporal lobe

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9
Q

how long before symptoms appear can the neuropathology occur?

A

10-20 years

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10
Q

What is the temporal lobe important for?

A

processing of semantics in speech and vision and key role in LTM

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11
Q

What is the first sign of AD?

A

memory loss

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12
Q

What can be seen in an MRI of an AD brain?

A
  • enlargement of the ventricles
  • hippocampal and cortical shrinkage
  • lesions on occipital lobe (visual hallucinations)
  • lesions on frontal lobe (decision making issues)
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13
Q

What further issues may become apparent in severe AD?

A

gait, incontinence, motor disturbances, bedridden and long term care needed

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14
Q

Where are b-amyloid plaques found?

A

outside the neurons

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15
Q

What are b-amyloid plaques?

A

insoluble aggregates of b-amyloid proteins

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16
Q

where are NFTs found?

A

inside the neurons

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17
Q

What are NFTs?

A

insoluble aggregates of hyperphosphorylated Tau

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18
Q

when can a confident diagnosis of AD be made?

A

at autopsy

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19
Q

How well can clinical criteria hope to identify AD?

A

sensitivity -80%

specificity - 70%

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20
Q

How is AD diagnosed?

A

Mini-mental status exam
History from family/friends
MRI and PET scans - rear brain inactivity
CSF markers - 300% increase in tau, Ab increase 50%

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21
Q

What can be found in APP null mice?

A

normalish - underweight and decreased activity

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22
Q

What can be found in APLP2 null mice?

A

normal

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23
Q

What can be found in APP/APLP2 null mice?

A

80% die within a week, deficits in balance and strength

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24
Q

What is the major pathway of b-amyloid production?

A

using a-secretase

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25
Q

What are the minor pathways of Ab production?

A

b/y secretases -> Ab peptide and APPb, P7

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26
Q

What is the y-secretase complex?

A

presenilin, nicastrin, presenilin enhancer

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27
Q

What can be seen with Ab 42 and Ab43?

A

preferentially form networks of salt linkages and strong hydrogen bonds between ionised side chains of opposite charge which form plaques

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28
Q

What form of Ab is increase in AD?

A

Ab1-42

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29
Q

How much does Ab1-42 normally make up in healthy individuals?

A

5-20%

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30
Q

What are some features of Ab1-42?

A

more hydrophobic
more prone to fibril formation
facilitated by Zn/Cu

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31
Q

Why are plaques not a definitive marker of AD?

A

healthy patients have them too

not all mice with AD have plaques

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32
Q

What is the evidence for Ab as a cause of AD?

A
  • increased no. of plaques in patients
  • genetic mutations in EOAD cause increased production of Ab peptides
  • Ab plaques appear in Down Syndrome that carry extra copy of APP gene
  • APOE4 increase risk of sporadic AD
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33
Q

Why is b-amyloid toxic?

A
  • can induce apoptosis in cultured cells
  • induces production of ROS -> apoptosis
  • may directly insert into and disrupt cellular membranes
  • may promote aggregation of tau to form NFTs
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34
Q

What is the b-amyloid hypothesis?

A

the accumulation of a fragment of APP or Ab1-42 leading to the formation of plaques that kill neurons

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35
Q

What is the tau hypothesis?

A

abnormal phosphorylation of tau proteins making them sticky and leading to the break up of microtubules
loss of axonal transport leads to cell death

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36
Q

What are the genetic mutations associated with EOAD?

A

PS1, PS2 and APP - increased production of Ab-peptide

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37
Q

Why are Down Syndrome patients at increased risk of AD?

A

carry an extra copy of the APP gene which is on Chromosome 21

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38
Q

Where does Tau bind?

A

microtubules, predominantly in the axons of neurons

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39
Q

What does tau co-purify with?

A

tubulin and microtubules

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40
Q

What does the co-existence of tau with tubulin and microtubules do?

A

stabilises MT integrity, promoting MT assembly which is responsible for transport of molecules within neurons

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41
Q

What is the function of microtubules?

A

transport of molecules within neurons

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42
Q

What are NFTs?

A

aggregated Tau

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43
Q

Where is Tau redistributed in AD?

A

cell bodies and dendritesw

44
Q

What question does the redistribution of tau raise?

A

is it tau that is toxic or loss of MT function

45
Q

What happens in Tau KO mice?

A

normal and show no obvious developmental, cognitive or neuronal polarity deficits

46
Q

What other form of dementia is caused by mutations in Tau?

A

Frontotemporal Dementia with Parkinsonism (FTDP-17)

47
Q

What can be concluded from the genetic studies into tau?

A

it is the presence of abnormal tau/NFTs rather than loss of function that contributes to AD development

48
Q

Where have Tau mutations not been found?

A

AD

49
Q

What shows a high correlation with the development of AD?

A

the number and location of NFTs

50
Q

Which Tau mutations have increased tendency to aggregate and form NFTs?

A

FTDP-17

51
Q

Why is Tau not necessarily the answer to NFTs and neurodegeneration in AD?

A

some AD can have neuronal loss in absence of NFTs and some FTDP-17 can have extensive degeneration with few NFTs

52
Q

What proteins aid Tau hyperphosphorylation in AD?

A

GSK3, CdK5, MAPK

53
Q

What does tau hyper-phosphorylation do?

A
  • affects its ability to bind MTs
  • promotes aggregation
  • forms NFTs
54
Q

What suggests that NFTs over plaques are the correct hypothesis?

A
  • it is never just plaques that appear

- show higher correlation with AD progression than plaques

55
Q

What is the difference between familial AD and FTDP17?

A

AD - mutations in APP processing molecules and have high levels of plaques and tangles
FTDP17 - never has plaques, only tangles

56
Q

What backs up that plaques are the issue in AD?

A

transgenic mice that express mutant APP develop plaques but not tangles however have cognitive deficits

57
Q

What does Ab injection into transgenic mutant Tau mice do?

A

accelerates tangle formation

58
Q

What does accumulation of phosphate on Tau proteins do?

A

causes “Paired Helical Filaments” that accumulate and lead to NFTs - PHFs are the main component in NFTs

59
Q

What is the probable cause of cell death with the Tau hypothesis?

A

the impaired axonal transport

60
Q

What is the process of plaque accumulation according to the amyloid hypothesis?

A

non-soluble fragment of APP accumulates and is deposited outside the cell
insoluble nature of Ab-42 helps to gather other protein fragments i.e. ApoE into plaques

61
Q

What are the potential mechanisms of cell death in the amyloid hypothesis?

A

the plaques or possible migration of Ab-42 out of the cell

62
Q

What genes are the subunits of y-secretase?

A

PSEN1 and PSEN2

63
Q

What is the Serial model?

A

when Ab -> p-tau -> synaptic loss -> cell loss

64
Q

What is the dual pathway model?

A

Ab + p-tau -> synaptic loss -> cell loss

65
Q

What is the leading perception in AD ?

A

AD is initiated by the primary amyloidosis which causes secondary tauopathies -> neurodegeneration. Tau causes the neurodegeneration but the process is initiated by Ab

66
Q

What is the Current theory in AD?

A

it is a multifactorial pathway

  • protein accumulation -> plaques and tangles
  • inflammation -> glial activation
  • lipid distribution - lipid membrane site of APP cleavage
67
Q

What is the size of ApoE?

A

34kDa, 299aa

68
Q

where is ApoE highly produced?

A

liver and brian

69
Q

What cells in the brain produce ApoE?

A

glial cells - astrocytes

70
Q

What are the common isoforms of ApoE?

A

E2 - cys 112, cys 158
E3 - cys 112, arg 158
E4 - arg 112, arg 158

71
Q

Which form of ApoE is a risk factor?

A

E4

72
Q

What form of ApoE is neuroprotective?

A

E2

73
Q

How does Ab cross the BBB?

A

LRP transporters

74
Q

How does ApoE influence Ab clearance?

A

Ab has an affinity for ApoE

75
Q

What is the proposed mechanisms of Ab removal via various ApoE?

A

Ab may have lower affinity for lipid bound ApoE4 than ApoE3 - reduced clearance

76
Q

What are areas containing a-secretase low in?

A

cholesterol

77
Q

What are areas containing b/y secretase high in?

A

cholesterol and sphingolipids

78
Q

What mediates Ab influx across the BBB?

A

RAGE

79
Q

What are the two major proteases involved in Ab degradation?

A

IDE and NEP

80
Q

Where are IDE and NEP found?

A

IDE in the cytoplasm

NEP - transmembrane with active site on EC domain

81
Q

What happens in mutations on IDE and NEP?

A

increased Ab accumulation

82
Q

What are the varying hypotheses in AD?

A
  • Ab-amyloid hypothesis - plaques due to overproduction/clearance
  • Ab-oligomer - soluble oligomers block induction of LTP
  • Presenilin - impaired presenilin functions due to mutations or Ab
  • Ca dysregulation - due to ageing, oxidative stress, Ab
  • lysosome hypothesis - lysosome/autophagy dysfunction
  • Tau hypothesis - aggregated hyperphosphorylated tau
83
Q

What are the mutations associated with EOAD?

A

mutations in APP, PS1, PS2 -> increase Ab 1-42 production

84
Q

What are the mutations associated with LOAD?

A

ApoE causing increase accumulation/decreased clearance of Ab1-42
IDE/NEP mutations

85
Q

What is the mulitfactorial threshold model?

A

many common alleles with low penetrance
most people have several risk factor
risk alleles are additive and environment additive factors
disease process begins when certain threshold is reached

86
Q

What are the features of APP mutations?

A

on chromosome 21
around 50yrs onset
5% families

87
Q

What are the features of the PS1 mutations?

A

chromosome 14
40 years onset
50% of families

88
Q

What are the features of PS2 mutations?

A

chromosome 1
40 years onset
rare

89
Q

What are the features of ApoE isoforms?

A

E4 decreases age of onset

chromosome 19

90
Q

What are the features of A2M?

A

a-macroglobulin
A2M-2 increased risk of AD
Chromosome 12

91
Q

What are the other risk factors of AD?

A

age, diabetes/obesity, brain activity, physical exercise

92
Q

What are the treatment goals in AD?

A

improve memory, functional status and behavioural symptoms
slow progression
delay or prevent onset

93
Q

Why are AChEIs given?

A

Acetylcholine transferases are lost early in AD progression in the cortex and hippocampus -> used to increase ACh in synapse

94
Q

What drugs may be given as AChEIs?

A

rivastigmine, donezepril, galantamine

95
Q

What are the effects seen with AChEI treatment?

A

modest improvement in memory and thinking in 50% AD patients
delays neurodegeneration by about 6 months
temporarily mitigates some of the symptoms

96
Q

What is used to target excitotoxicity in moderate-severe AD?

A

Memantine, glutamate receptor antagonist (NMDARs)

97
Q

What are considered the potential targets of future therapeutic needs in AD?

A

amyloid at the point of production, plaque build up or clearance

98
Q

What have NSAIDs been shown to do?

A

favour production of 1-40 over 1-42 via altered y-secretase activity

99
Q

Why is y-secretase a more difficult target?

A

has multiple essential substrates

100
Q

What enhances a-secretase activity and via what mechanisms?

A

bryostatin via PKC inhibition

101
Q

What other potential mechanisms could be targeted?

A

b-secretase - lacks other substrates
preventing aggregation - cluoquinol
immunotherapy for removal of Ab peptides/plaques

102
Q

What is cluoquinol?

A

an antibiotic and Cu/Zn chelator

103
Q

why did the AD vaccine fail?

A

due to encephalitis

104
Q

What are the research handicaps in developing AD therapies?

A

inconsistent results
inappropriate tools
inappropriate conclusions

105
Q

What does a good AD model need to show?

A

face validity - plaques/tangles/degeneration/cognitive loss
Reliability/reproducibility - consistent results between animals
Construct validity - observed in different environments w. different tests in the same species measuring the same things
Predictive validity - temporal relevance to the disease and treatment aimed at the insult

Applied Neuroanatomy (11 decks)

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