Alzheimers Disease Flashcards
1
Q
what is dementia?
A
an irreversible, progressive brain disease that slowly destroys memory and cognitive skills
2
Q
What may dementia affect?
A
comprehension, calculation, learning, language, judgement and potentially also personality, mood, behaviour and motivation
3
Q
what is the mean survival following AD diagnosis?
A
7 years
4
Q
What is the commonality in 80+ year olds?
A
1 in 5
5
Q
How common is AD in terms of dementias?
A
55%
6
Q
Where are signs of AD first noticed in the brain?
A
Enterohinal cortex
7
Q
Where does AD progress to from the enterohinal cortex?
A
hippocampus
8
Q
What is the enterohinal cortex a part of ?
A
the temporal lobe
9
Q
how long before symptoms appear can the neuropathology occur?
A
10-20 years
10
Q
What is the temporal lobe important for?
A
processing of semantics in speech and vision and key role in LTM
11
Q
What is the first sign of AD?
A
memory loss
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)
13
Q
What further issues may become apparent in severe AD?
A
gait, incontinence, motor disturbances, bedridden and long term care needed
14
Q
Where are b-amyloid plaques found?
A
outside the neurons
15
Q
What are b-amyloid plaques?
A
insoluble aggregates of b-amyloid proteins
16
Q
where are NFTs found?
A
inside the neurons
17
Q
What are NFTs?
A
insoluble aggregates of hyperphosphorylated Tau
18
Q
when can a confident diagnosis of AD be made?
A
at autopsy
19
Q
How well can clinical criteria hope to identify AD?
A
sensitivity -80%
specificity - 70%
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%
21
Q
What can be found in APP null mice?
A
normalish - underweight and decreased activity
22
Q
What can be found in APLP2 null mice?
A
normal
23
Q
What can be found in APP/APLP2 null mice?
A
80% die within a week, deficits in balance and strength
24
Q
What is the major pathway of b-amyloid production?
A
using a-secretase
25
What are the minor pathways of Ab production?
b/y secretases -> Ab peptide and APPb, P7
26
What is the y-secretase complex?
presenilin, nicastrin, presenilin enhancer
27
What can be seen with Ab 42 and Ab43?
preferentially form networks of salt linkages and strong hydrogen bonds between ionised side chains of opposite charge which form plaques
28
What form of Ab is increase in AD?
Ab1-42
29
How much does Ab1-42 normally make up in healthy individuals?
5-20%
30
What are some features of Ab1-42?
more hydrophobic
more prone to fibril formation
facilitated by Zn/Cu
31
Why are plaques not a definitive marker of AD?
healthy patients have them too
| not all mice with AD have plaques
32
What is the evidence for Ab as a cause of AD?
- 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
33
Why is b-amyloid toxic?
- 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
34
What is the b-amyloid hypothesis?
the accumulation of a fragment of APP or Ab1-42 leading to the formation of plaques that kill neurons
35
What is the tau hypothesis?
abnormal phosphorylation of tau proteins making them sticky and leading to the break up of microtubules
loss of axonal transport leads to cell death
36
What are the genetic mutations associated with EOAD?
PS1, PS2 and APP - increased production of Ab-peptide
37
Why are Down Syndrome patients at increased risk of AD?
carry an extra copy of the APP gene which is on Chromosome 21
38
Where does Tau bind?
microtubules, predominantly in the axons of neurons
39
What does tau co-purify with?
tubulin and microtubules
40
What does the co-existence of tau with tubulin and microtubules do?
stabilises MT integrity, promoting MT assembly which is responsible for transport of molecules within neurons
41
What is the function of microtubules?
transport of molecules within neurons
42
What are NFTs?
aggregated Tau
43
Where is Tau redistributed in AD?
cell bodies and dendritesw
44
What question does the redistribution of tau raise?
is it tau that is toxic or loss of MT function
45
What happens in Tau KO mice?
normal and show no obvious developmental, cognitive or neuronal polarity deficits
46
What other form of dementia is caused by mutations in Tau?
Frontotemporal Dementia with Parkinsonism (FTDP-17)
47
What can be concluded from the genetic studies into tau?
it is the presence of abnormal tau/NFTs rather than loss of function that contributes to AD development
48
Where have Tau mutations not been found?
AD
49
What shows a high correlation with the development of AD?
the number and location of NFTs
50
Which Tau mutations have increased tendency to aggregate and form NFTs?
FTDP-17
51
Why is Tau not necessarily the answer to NFTs and neurodegeneration in AD?
some AD can have neuronal loss in absence of NFTs and some FTDP-17 can have extensive degeneration with few NFTs
52
What proteins aid Tau hyperphosphorylation in AD?
GSK3, CdK5, MAPK
53
What does tau hyper-phosphorylation do?
- affects its ability to bind MTs
- promotes aggregation
- forms NFTs
54
What suggests that NFTs over plaques are the correct hypothesis?
- it is never just plaques that appear
| - show higher correlation with AD progression than plaques
55
What is the difference between familial AD and FTDP17?
AD - mutations in APP processing molecules and have high levels of plaques and tangles
FTDP17 - never has plaques, only tangles
56
What backs up that plaques are the issue in AD?
transgenic mice that express mutant APP develop plaques but not tangles however have cognitive deficits
57
What does Ab injection into transgenic mutant Tau mice do?
accelerates tangle formation
58
What does accumulation of phosphate on Tau proteins do?
causes "Paired Helical Filaments" that accumulate and lead to NFTs - PHFs are the main component in NFTs
59
What is the probable cause of cell death with the Tau hypothesis?
the impaired axonal transport
60
What is the process of plaque accumulation according to the amyloid hypothesis?
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
What are the potential mechanisms of cell death in the amyloid hypothesis?
the plaques or possible migration of Ab-42 out of the cell
62
What genes are the subunits of y-secretase?
PSEN1 and PSEN2
63
What is the Serial model?
when Ab -> p-tau -> synaptic loss -> cell loss
64
What is the dual pathway model?
Ab + p-tau -> synaptic loss -> cell loss
65
What is the leading perception in AD ?
AD is initiated by the primary amyloidosis which causes secondary tauopathies -> neurodegeneration. Tau causes the neurodegeneration but the process is initiated by Ab
66
What is the Current theory in AD?
it is a multifactorial pathway
- protein accumulation -> plaques and tangles
- inflammation -> glial activation
- lipid distribution - lipid membrane site of APP cleavage
67
What is the size of ApoE?
34kDa, 299aa
68
where is ApoE highly produced?
liver and brian
69
What cells in the brain produce ApoE?
glial cells - astrocytes
70
What are the common isoforms of ApoE?
E2 - cys 112, cys 158
E3 - cys 112, arg 158
E4 - arg 112, arg 158
71
Which form of ApoE is a risk factor?
E4
72
What form of ApoE is neuroprotective?
E2
73
How does Ab cross the BBB?
LRP transporters
74
How does ApoE influence Ab clearance?
Ab has an affinity for ApoE
75
What is the proposed mechanisms of Ab removal via various ApoE?
Ab may have lower affinity for lipid bound ApoE4 than ApoE3 - reduced clearance
76
What are areas containing a-secretase low in?
cholesterol
77
What are areas containing b/y secretase high in?
cholesterol and sphingolipids
78
What mediates Ab influx across the BBB?
RAGE
79
What are the two major proteases involved in Ab degradation?
IDE and NEP
80
Where are IDE and NEP found?
IDE in the cytoplasm
| NEP - transmembrane with active site on EC domain
81
What happens in mutations on IDE and NEP?
increased Ab accumulation
82
What are the varying hypotheses in AD?
- 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
What are the mutations associated with EOAD?
mutations in APP, PS1, PS2 -> increase Ab 1-42 production
84
What are the mutations associated with LOAD?
ApoE causing increase accumulation/decreased clearance of Ab1-42
IDE/NEP mutations
85
What is the mulitfactorial threshold model?
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
What are the features of APP mutations?
on chromosome 21
around 50yrs onset
5% families
87
What are the features of the PS1 mutations?
chromosome 14
40 years onset
50% of families
88
What are the features of PS2 mutations?
chromosome 1
40 years onset
rare
89
What are the features of ApoE isoforms?
E4 decreases age of onset
| chromosome 19
90
What are the features of A2M?
a-macroglobulin
A2M-2 increased risk of AD
Chromosome 12
91
What are the other risk factors of AD?
age, diabetes/obesity, brain activity, physical exercise
92
What are the treatment goals in AD?
improve memory, functional status and behavioural symptoms
slow progression
delay or prevent onset
93
Why are AChEIs given?
Acetylcholine transferases are lost early in AD progression in the cortex and hippocampus -> used to increase ACh in synapse
94
What drugs may be given as AChEIs?
rivastigmine, donezepril, galantamine
95
What are the effects seen with AChEI treatment?
modest improvement in memory and thinking in 50% AD patients
delays neurodegeneration by about 6 months
temporarily mitigates some of the symptoms
96
What is used to target excitotoxicity in moderate-severe AD?
Memantine, glutamate receptor antagonist (NMDARs)
97
What are considered the potential targets of future therapeutic needs in AD?
amyloid at the point of production, plaque build up or clearance
98
What have NSAIDs been shown to do?
favour production of 1-40 over 1-42 via altered y-secretase activity
99
Why is y-secretase a more difficult target?
has multiple essential substrates
100
What enhances a-secretase activity and via what mechanisms?
bryostatin via PKC inhibition
101
What other potential mechanisms could be targeted?
b-secretase - lacks other substrates
preventing aggregation - cluoquinol
immunotherapy for removal of Ab peptides/plaques
102
What is cluoquinol?
an antibiotic and Cu/Zn chelator
103
why did the AD vaccine fail?
due to encephalitis
104
What are the research handicaps in developing AD therapies?
inconsistent results
inappropriate tools
inappropriate conclusions
105
What does a good AD model need to show?
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
