Williamson - Alzheimer's Disease Flashcards
(81 cards)
1
Q
How common is AD, comp to other dementias?
A
- most common = 60-70%
2
Q
What is the 1st symptom of AD?
A
- loss of ST memory
3
Q
What are later symptoms of AD?
A
- disorientation, mood swings, delusions and apathy, leading to withdrawal
4
Q
What is the av LE after diagnosis w/ AD?
A
- 3-9 yrs
5
Q
Does AD have a genetic basis generally?
A
- some cases w/ clear genetic basis, but in most cases weak –> sporadic occurrence
6
Q
How is AD most clearly diagnosed?
A
- examination of brain after death
7
Q
What is seen when examining an AD brain?
A
- major death of cells and shrinkage
- typically lose parts assoc w/ language and higher order functions
- on closer examination can see plaques surrounding outside of neurons –> made of prot (Aβ)
8
Q
How long is Aβ?
A
- v short –> only 39-42 res
9
Q
What can you often see inside neurons of those affected?
A
- neurofibrillary tangles (prot ppts inside neurons) –> hyperphos form of tau prot, tau binds microtubules and stabilises them (can’t do this if tangled, would interfere w/ signalling along axons)
10
Q
How is Aβ made?
A
- cut out of middle of much longer prot = amyloid precursor prot (APP)
11
Q
What is the structure of APP?
A
- TM region, short intracellular part at C-ter and much longer globular bit outside cell at N-ter end
- looks like receptor
12
Q
What is the function of APP?
A
- not known –> poss to do w/ metal ion reg in brain or to do w/ learning (synapse formation)?
13
Q
What is the effect of APP KOs in animals?
A
- look and function fairly normally
14
Q
What is the role of α secretase?
A
- cuts APP in middle of Aβ seq, so lowers amount of it (GOOD)
15
Q
What fam is α secretase part of?
A
- ADAMs
16
Q
What happens if APP cut by β secretase (BACE)?
A
- creates ec fragment and tm fragment, tm fragment not then cut by α secretase, but by γ secretase
17
Q
Where does γ secretase cut APP?
A
- cuts in middle of membrane, rich in cholesterol, so dep on whether enough cholesterol in right place
18
Q
What is presenilin, and what is its role?
A
- sub component of γ secretase that’s responsible for cutting APP
19
Q
How were presenilin genes discovered?
A
- by linkage studies in familial AD (discovered indep)
20
Q
What is the result of cleavage by γ secretase?
A
- prod peptide that is either 40 or 42 residues long: Aβ(1-40) or Aβ(1-42) → 1-42 more prone to aggreg and more toxic
21
Q
What determines where γ secretase cuts, and therefore disease progression?
A
- the fact it is a complex of enzs
22
Q
Does the presence of plaques alone result in AD?
A
- no, everyone makes Aβ in brain and elsewhere
- as you age everyone has plaques in brain, in some this process prod AD (ie. having plaques doesn’t mean you have AD, so prob not directly cause, but is 1 of main symptoms so def connected)
23
Q
How do early onset cases of AD differ?
A
- more of a genetic element
- tend to be more severe and progress more
24
Q
Generally, what is the amyloid cascade hypothesis?
A
- AD caused by overprod of Aβ
- collects into plaques and plaques in some way toxic
25
What does the amyloid cascade hypothesis could be a potential way to treat AD?
- reduction in amount of Aβ
26
Where is the APP gene located, and what is the consequence of this?
- on chromosome 21
| - Down's patients typically all have early onset AD (age 40-50)
27
What is the strongest genetic risk factor for AD?
- allele of apolipoprotein E (ApoE4)
| - increases risk 3x in heterozygotes and 15x in homozygotes
28
What is the role of ApoE and does this support the amyloid cascade hypothesis?
- ApoE transports cholesterol to neurons
- most likely reason for assoc is that ApoE helps remove or break down Aβ and E4 is worst at this
- strongly supports amyloid cascade hypothesis --> ie. suggests AD is an amyloid disease
29
How many amyloid diseases are there?
- 30 major ones
30
What characterises amyloid diseases?
- naturally occurring prot (normally globular and well understood function) unfolds, misfolds, aggregates and collects in fibrous plaques (if unfold always risk of binding other unfolded prots)
- ie. protein misfolding disease
- plaques always formed of β sheet prot, all form cross in X-ray beam, indicating repeated structure every 4.7Å in 1 direction and 10Å at right angles --> caused by parallel β strands running at right angles to fibre direction (cross-β)
31
Can any prot form amyloid fibres?
- basically any prot can misfold to form amyloid fibres if treat badly, as all prots unfold occasionally (as quite a stable structure) --> need to have at high conc and destab native fold
32
If amyloid was really harmful why have we not evolved function to remove?
- evo isn't really concerned w/ elderly --> as already performed function of prod offspring
33
What characterises systemic amyloid disease (SAD)?
- body prod excessive amounts of Ab L chains, which accum as amyloid deposits in diff tissues (esp kidneys --> become waxy and enlarged)
- also builds up in heart, causing heart failure
34
What is the role role of acute phase prots, and an eg. relating to amyloid?
- prots prod by body to deal w/ inflam
- eg. lots of innate immunity prots
- eg. serum amyloid A, recruits immune cells and transports cholesterol to liver, upreg in chronic inflam (eg. rheumatoid arthritis), so builds up, can prod amyloid deposits in kidneys
35
How can dialysis lead to amyloid disease?
- doesn’t remove prots (too big for dialysis filters), so prots build up w/ LT dialysis
- eg. β2 microglobulin, a component of MHCI (maybe dialysis destab it?)
- builds up in organs and joints = dialysis related amyloidogenesis
- after recognised, treated and no longer a problem
36
What is an iatrogenic disease, and an eg.?
- when medical intervention leads to a further disease
| - eg. dialysis leading to amyloidogenesis
37
How is TIID related to amyloid disease?
- IAPP helps insulin work
- IAPP exp at same time as insulin (and 100x more)
- body therefore makes lots of IAPP and diabetes patients tend to get amyloid deposits of IAPP in islet cells
38
Is AD related to no. plaques?
- roughly true --> not strong relationship, but better than NFTs
39
Why might we not be seeing a strong correl between AD and no. plaques?
- could be looking at wrong part of brain
| - or not seeing all plaques
40
What mouse model can we make for AD?
- can make transgenic mice w/ mutant human APP (that predisposes humans to AD)
- so overexpression of Aβ in mice, so have plaques, also “have AD” (ie. run slower, worse at finding submerged platform in water)
41
What are some problems w/ animal models of AD?
- in humans AD takes 60 years to start, so is behaviour in 16 mo mice showing same thing?
- how reliably can we say behaviour in mice is AD?
42
What effects do plaques have in the brain?
- seem to cause local inflam, treated by body as foreign, so to some extent cause body to attack own neurons and kill them
- also stim prod of ROS, leading to local inflam and tissue damage, vascular degen etc.
43
What happens if a plaque forms across a synapse?
- doesn't block it (ie. not physically blocking nerve transmission) --> this isn't why they are damaging
44
Where do amyloid oligomers fit into the pathway?
- when form Aβ fibres, typically on the way to the fibre get Aβ oligomers
- if you leave long enough will form fibre
- not clear if ‘on pathway’ to fibrils or ‘off pathway’ (does it have to go back to monomer before can become fibre?)
45
What is the morphology of amyloid oligomers?
- don't have well defined shape or size or appearance (vary in this and density)
46
What have lots of experiments shown about oligomers, and what is now the most popular theory?
- oligomers are more toxic than mature fibrils or protofibrils
- toxic species is oligomers
47
Why does it make sense that oligomers are the toxic species?
- smaller so have more ‘ends’ to build on (storehouse of available monomer, give monomer to fibres, so could be toxic as has so much available monomer, where as it isn't in a fibre) --> to get fibre need short bit and add monomers on the end (so need lots of Aβ)
48
Should drugs target and destroy fibres?
- if destroy fibres then making more monomers, so is this making it worse?
- good if fibres toxic, bad if oligomers toxic
- maybe want to turn all oligomers into fibres, so there is none available?
49
What are some other theories as to why oligomers are toxic
- oligomers bind to membranes, in vitro oligomers can make artificial membranes permeable
- maybe oligomers that build up on membranes are diff from those that build up in vitro in solution, evidence:
- -> fibrils grown on membrane surfaces look and behave diff
- -> Aβ binds to lipid rafts formed of cholesterol and GM1 (= ganglioside, a common brain lipid)
- -> so could it be that ‘membrane oligomers’ are diff and more toxic
50
What is the role of Tau, and how might it play a role in AD?
- reg microtubule assembly and disassembly, so involved in stab
- transport along axons needs microtubules, so if messed up don’t get neurotransmission
- so an obvious reason might get brain damage occurring in AD
51
Which comes 1st Aβ changes or tau?
- debate, but most think that Aβ changes comes before tau
52
How is tau phos reg?
- balance between kinases and phosphatases --> may be that Aβ alt activities of these enzymes, esp the phosphatases
53
How might Aβ interact w/ tau?
- recent results suggest Aβ can interact w/ certain receptors on neuronal membrane and prod ic signals
- this may be how Aβ affects tau and how Aβ is toxic
54
What are the diff approaches for AD therapies?
- stabilise monomer
- stabilise off pathway oligomer
- prevent fibrillisation
- dissoc fibrils
- refold aggregates
- get rid of aggregates --> if have Ab against Aβ would be good treatment
55
What are the diff stages of drug trials, and what is their purpose?
- preclinical = to show affects biochem in way expected
- clinical:
- -> phase 1 = small scale on healthy volunteers - toxicity, approp doses
- -> phase 2 = small scale on patients - does it work, safety
- -> phase 3 = large scale on lots of patients - does it work, side effects
56
Why do drug trials for AD take so long, and how long are they tested for?
- need to test LT
- drugs intended to improve symptoms = 6-12 mo (longer if looking for stabilisation)
- drugs intended to prod cure = 18-24 mo
57
What is gen measured in AD trials?
- severity, cognitive performance (standardised scores), needs signif improvement --> sensitive measure and/or lots of patients
- more recently also tested biomarkers, eg. Aβ or tau in cerebrospinal fluid, brain imaging for amyloid or brain vol --> might allow earlier detection
58
What are the questions surrounding how 'good' a drug needs to be to be approved?
- if a drug only slows down onset, should it be used? (this is all current drugs on market do)
- how big a difference do you need? (how much more must it slow down progression that current drugs)
59
What do the current drugs for AD do?
- affect neurotransmitters
- -> AD causes death of neurons and loss of connections, so can slow effects by strengthening signalling across synapse, esp cholinergic (ie. use inhib of cholinesterase, which cleaves ACh)
- -> maintain cognitive function for longer (only affect symptoms)
- also drugs to help behavioral symptoms --> often antipsychotics or antidepressants
60
Why could the secretases be good drug targets?
- know lots about inhibiting proteases
- would reduce Aβ prod
- cheaper and simpler than biologics
61
How would each secretase be targeted?
- want to increase α secretase activity (as cleaves in middle of Aβ) --> but harder to look for drug to increase enzyme activity
- β secretase inhibitor --> as 1st step in prod Aβ
- γ secretase --> better if made more 1-40
62
What is the issue w/ targeting γ secretase?
- if inhibit γ secretase would KO notch signalling --> v serious problems, unless could deliver specifically to brain
63
What attempts have been made to target γ secretase?
- attempts to target not active site itself, but docking site for APP or reg site, or try to influence where it cuts C-ter end
- NSAIDs do seem to change specificity, so makes more Aβ(1-40) and less of more toxic Aβ(1-42)
64
What are the diff ways in which the amyloid cascade can be targeted (ie. what parts)?
- secretases
- removal of Aβ aggregates
- prevent build of Aβ aggregates
- vaccines against Aβ(1-42)
- reduce cholesterol
65
How could Aβ aggregates be removed as a treatment, and what have been some problems?
- immunise using Aβ(1-42) and get IS to do work --> reduced amyloid plaques, but 6% patients dev meningoencephalitis (brain inflam)
- so may not be good completely removing Aβ, dont know its full role, may need some for some reason
- OR Ab that specifically recognises amyloid aggregates of Aβ and not Aβ monomers --> trials ongoing, but many halted due to lack of efficacy
66
What are the advs/disadvs of biologics?
- most traditional drugs are taken orally --> these are more difficult to administer
- more expensive to make/buy
- but more specific and if works best?
67
How could the build of Aβ aggregates be used as a target for treatment, what are the issues?
- several are NSAIDS (safe, know cross blood-brain barrier)
- so far none successful
- BUT if toxic species are oligomers, maybe best not to prevent aggregation, to steer Aβ out of oligomers into ‘harmless’ plaques?
68
How could tau be targeted for AD treatment, any success?
- inhibit enzs involved in tau phos, inhibit taau aggreg, stab microtubules
- ongoing trials (major one halted due to lack of efficacy)
69
Why is ApoE4 a complicated target?
- as not clear why its linked
70
What is the consequence of the fact that a surprising no. drug trials made symptoms worse, what should we be looking at now?
- maybe we don't really understand AD
- Aβ aggregates induce inflam, stim ROS, maybe these cause problems, use antioxidants?
- or maybe should be looking more generally at vascular health
- should we not be looking for ‘magic bullet’ (targeting v specific process) at all --> but should we look at chemicals w/ multiple sites, eg. NSAID or polyphenols like EGCG (from green tea)?
- maybe it's western diet etc., so should combine w/ move healthier lifestyle/foods?
71
What hormone does PD affect?
- dopamine
72
How does PD differ to AD?
- kills diff regions of brain
73
What is the amyloid prot involved in PD?
- α-synuclein
| - collects inside neurons in ‘Lewy bodies’
74
How much of brain has to have died before PD recognised?
- around 80%
75
What are the genetic factors leading to PD?
- gene for α-synuclein --> function not clear (organisation of presynaptic vesicles?), a common prot (up to 1% of all neuronal prot)
- gene for Leu rich repeat kinase LRRK2 (aka PARK8) --> function unclear but assoc w/ maintenance of dendrite structure, no clear connection to PD
- several others, but no obvious clues except for inflam
- reported that TMEM230 is linked --> encodes tm prot of secretory/recycling vesicles, inc synaptic vesicles in neurons (ie. a defect in synaptic vesicles)
76
What does a link between the gut microbiome and PD suggest?
- implies some kind of signalling between gut and brain
77
What is the structure of α-synuclein in vivo?
- v big and intrinsically disordered
78
Are IPDs common, and what is there apparent role?
- roughly 1/3 prot seq and 25% human genes predicted to be disordered
- lot of IDPs assoc w/ signalling
- must be functional or body wouldn't make them
79
Why are IPDs more likely to form amyloid?
- as do not need to unfold 1st, so lower energy barrier to forming amyloid
80
What env factors may contrib to PD?
- pesticides, head injury, metals (but evidence not convincing)
- some chemicals seem to protect, eg. coffee, NSAIDs, smoking
- epigenetic link w/ DNA meth
- some connection to mt damage?
81
What drugs are there for PD?
- some drugs to slow PD, but no cure
- improve synaptic signalling, eg. L-DOPA (biosynthetic precursor of dopamine) --> dopamine cannot cross blood-brain barrier, unlike L-DOPA
