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Protein Folding and Misfolding in Disease > Alzheimer's > Flashcards

Alzheimer's Flashcards

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1
Q

Senile dementia

A

a type of disease that causes the to brain stop functioning properly

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2
Q

What percentage of senile dementia’s are Alzheimer’s?

A

60-70%

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3
Q

How long does Alzheimer’s develop over?

A

3-9 years

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4
Q

What is the first-symptom of AD?

A

Short-term memory loss
- difficult to detect

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5
Q

What are the later symptoms of AD?

A

Disorientation
Mood swings
Delusions
Apathy
Loss of speech

There is no cure

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6
Q

Causes of Alzheimer’s

A

Incidence increases with age

Some cases have a clear genetic basis, genes that pre-dispose you to Alzheimer’s
But for most there is no genetic link

Increasing prevalence of AD is due to people living longer

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7
Q

AD diagnosis

A

Can be diagnosed by behavioural changes BUT these are true of any dementia

AD most clearly diagnosed by examination of brain after death
- major death of cells and shrinkage

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8
Q

Kills off specific regions of brain cells:

A

Hippocampus

Ventricles

Cortex

Language centres

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9
Q

Hippocampus

A

Vital for learning, memory and spatial navigation (explains disorientation)

In AD: shrink severely

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10
Q

Ventricles

A

Fill with cerebrospinal fluid

In AD: grow larger
reflective of a loss of brain tissue

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11
Q

Cortex

A

Involved in thinking, planning and remembering

In AD: shrivels up

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12
Q

What proteins form amyloid plaques in AD?

A

Amyloid-beta (A-beta) proteins
39-43 residues long

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13
Q

Characteristic protein deposits of AD

A

A-beta plaques surround the neurons (outside of brain cells)

Neurofibrillary tangles

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14
Q

How does AD differ from a typical amyloid disease?

A

Normally amyloid disease is caused by plaque physically causing a blockage

AD is not caused by the plaque - it is not blockage that causes cell death

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15
Q

Why are neurodegenerative diseases so dangerous?

A

Brain cells are post-mitotic so don’t get replaces EVER

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16
Q

Neurofibrillary tangles

A

Caused by a hyperphosphorylated form of protein tau

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17
Q

tau

A

Binds to microtubules and stabilises them

Microtubules are essential for neuron function as neurones are very large cells and this is how things are transported up and down the axon

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18
Q

AD affect on tau

A

tau hyperphosphorylate –> messes up microtubules –> neuron can’t function –> neuron dies

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19
Q

A-beta affect on tau

A

A-beta accelerates hyperphosphorylation of tau by mediating the activation of protein kinases

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20
Q

Examples of two protein kinases activated by A-beta to phosphorylate tau

A

CDK-5

GSK-3beta

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21
Q

A-beta production

A

Cut from amyloid precursor protein (APP)

Three proteases involved in cutting APP
- alpha-secretase
- beta-secretase
- gamma-secretase (presenilin)

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22
Q

alpha-secretase

A

THE GOOD ONE
The major protease that acts most of the time

Cuts in the middle of A-beta sequence of APP
reduces the production of A-beta

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23
Q

beta-secretase

A

Cuts APP
Creates exc. fragment and TM fragment

works with gamma-secretase

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24
Q

gamma-secretase

A

Membrane protein
Cuts TM fragment to produce a peptide either 40 or 42 residues long

Product is either:
A-beta (1-40)
A-beta (1-42)

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25
A-beta (1-42)
Extra two residues at C-terminus are isoleucine and alanine - hydrophobic residues - more prone to aggregation more toxic peptide
26
Early onset AD
Occurs <65 y/o Strong genetic element that causes it
27
Genetic element of EOAD
Mainly caused by mutations in gene for APP or presenilin 1 and 2
28
Amyloid cascade hypothesis
Caused by overproduction of A-beta which collects into plaques and the plaques are in some way toxic
29
APP gene
On chromosome 21
30
Trisomy of chromosome 21
Causes down syndrome Down-syndrome people typically all get EOAD Extra copy of chromosome 21 means that they're making 50% more A-beta than everybody else
31
Distal chromosome 21 trisomy
Causes down syndrome Do NOT get EOAD - APP gene is on the other end of the chromosome
32
Genetic risk factor for AD
Allele of alipoprotein E: epsilon-4 (ApoE4)
33
ApoE
Protein that transports lipids around the body Transports cholesterol to neurons
34
ApoE4
Allele of ApoE protein People with this allele are more likely to get AD Most likely association is that ApoE helps remove or break down A-beta and ApoE4 is worst at this
35
Correlation between number of plaques and AD severity
Roughly true that more plaques leads to increased severity
36
Correlation between number of neurofibrillary fibres and AD severity
Stronger relationship than with number of plaques Messes up amyloid cascade hypothesis
37
Animal models used for AD
Transgenic mice with mutant form of human APP - they get plaques and AD
38
Problem with animal model of AD
Difficult to reliably say behaviour in a mouse is caused by AD
39
Role of plaques in AD
Recognised by microglial cells in brain, causing local inflammation Inflammation leads to release of reactive oxygen species by immune cells - causes tissue damage, vascualr degeneration, etc Plaques are contributing to AD but NOT causing it
40
Amyloid oligomers
Aggregate of a small number of particles (20ish monomers) More toxic than mature fibrils or protofibrils Oligomers are causing AD
41
Oligomers ON pathway
Plaque formation pathway has to go through oligomer formation monomer --> oligomer --> protofibrils --> fibres oligomers somehow rearrange themselves and turn into fibres
42
Oligomers OFF pathway
Plaque formation pathway does NOT have to go through oligomers Oligomers just store monomers; provide a higher concentration of monomer at once
43
What is required for monomers to aggregate?
In order for monomers to aggregate there needs to be: a high concentration AND a folding nucleus
44
Folding-nucleus
Can be pre-existing fibres formed of amyloid monomers Surface is the right shape to bind more monomers Monomers then fall off and start making a new fibre
45
Therapies targeting A-beta fibres
Targeted due to amyloid-cascade hypothesis BUT If fibres aren't causing AD then removal of them is making more oligomers Removes the folding nucleus for fibre synthesis
46
tau phosphorylation
Phosphorylation of tau at multiple Ser/Thr sites Controlled by kinases and phosphatases, these are signalling molecules So, controlled by receptors and signalling processes
47
What are current therapies in phase 3?
18% Treat neuropsychiatric symptoms 21% Symptomatic cognitive enhancers - help neuronal symptoms i.e. mood swings, loss of language 61% are Disease modifying therapies (DMTs)
48
Example of symptomatic cognitive enhancer
Cholinesterase inhibitors working to boost Ach levels in the brain Block acetylcholinesterase that break down Ach
49
Different types of DMT
Majority are attacking amyloid Targeting oxidative stress - reactive oxidative species Targeting gut-brain axis Targeting tau Controlling inflammation
50
Gut-brain axis
theory suggesting communication between gut microbiome and brain, controls brain function
51
Success in AD therapies
Many attempt but not very good No new drugs approved in Europe since 2002
52
Drug Trials
Preclinical: Show that it affects biochemistry in expected way - using assays, cell lines, animal models Clinical: Phase 1, 2 and 3
53
Phase 1
small scale of healthy volunteers assess safety/toxicity determine dosage
54
Phase 2
several hundred participants that have the disease evaluate safety and immunogenicity optimise dosage DOES IT WORK
55
Phase 3
Large scale on lots more patients DOES IT WORK Side effects
56
Challenges in AD trials
Getting informed consent from volunteers with AD Drug intended to improve symptoms run for 6-12 months Drugs intended to produce cure run for 18-24 months
57
Methods of measuring AD severity
Cognitive performance - not very quantitative or reliable Biomarkers specific to an indicator of AD such as A-beta or hyperphosphorylated tau
58
Affect of AD
Kills brain cells Kills transmission of neural signals Specifically Ach neurotransmitter
59
Existing drugs for AD
Slow down the breakdown of Ach in synapse so the signal lasts longer
60
Target 1: alpha-secretase
Start of amyloid cascade - prevent amyloid formation alpha: no genetic link to AD, would need to increase activity of enzyme, not decrease (difficult) Some drugs in trial i.e. EGCG
61
Target 1: beta-secretase
hasn't worked so far
62
Target 1: gamma-secretase
Start of amyloid cascade - prevent amyloid formation best hope BUT also cleaves signalling receptor, Notch, that is involved in cell development inhibition would have effects all over the body - would need to deliver directly to the brain
63
NSAIDs effect on gamma-secretase
make it change its preference to make more A-beta (1-40) and less, toxic A-beta (1-42) Does NOT affect Notch cleavage
64
Target 2: End of amyloid cascade
getting rid of A-beta aggregates Active immunisation Passive Immunisation
65
Active immunisation
Immunise using A-beta (1-42) Get the immune system to do the work
66
Effect of active immunisation therapy
Appears to reduce amyloid plaques BUT 6% patients developed meningoencephalitis - inflammed brain
67
Passive immunisation
Give several antibodies against A-beta Do reduce the amount of A-beta aggregates and so slow down AD progression BUT do not improve it
68
Name three drug therapies that use passive immunisation
Aducanumab Lecanemab Donanemab - all target A-beta aggregates (plaques)
69
Aducanumab
Trials were halted due to lack of results Not approved in Europe or UK
70
Lecanemab
Target A-beta fibrils before plaque formation Approved by the FDA in 2023 - decision opposed by patients group on grounds that it had little benefit and was not safe Not approved in Europe or UK
71
Donanemab
Produced by Eli Lilly 1/3 patients experienced amyloid related imaging abnormalities (ARIA)
72
ARIA
Amyloid-related imaging abnormalities MRI images indicating swelling or bleeding in the brain Found in 1/3 of patients for donanemab Also caused by lecanemab
73
Difference in mab therapies
Target different epitopes and behave differently against monomer, oligomers and fibres Aducanumab was the most specific for fibrils and the best at preventing secondary nucleation - formation of new fibres using old ones as catalysts
74
Possible consequences of preventing secondary nucleation
If oligomers are ON pathway - breaking up fibres will remove some of the toxic stuff If oligomers are OFF pathway - breaking up fibres will make more oligomers and monomers - spread and worsen the disease
75
Target 3: UPR
Excessive UPR leads to apoptosis of messed up cells - related to brain death in advanced AD UPR also induces inflammatory response Can use PERK inhibitors to prevent downstream neurodegeneration
76
PERK inhibitors
Shown to prevent neurodegeneration in mice with prions disease and on mice with dementia caused by tau deposits Stops UPR --> doesn't affect amyloid Still have amyloid plaques but prevents neurodegeneration
77
Target 4: Amyloid cascade
Link to ApoE4 Reduce cholesterol through the use of statins Could restructure brain membranes and possibly affect gamma-secretase Trials are ongoing
78
Target 5: tau
Many possibilities: Inhibit enzymes involved in phosphorylation Inhibit tau aggregation Stabilise microtubules
79
Astrocytes
Important cell in CNS Have an essential role in neuronal maintenance and A-beta clearance
80
Reactive astrocytes
Changed to reactive astrocytes by polarisation Induce neuropathy and neurodegeneration
81
Types of reactive astrocytes
A1 Pro-inflammatory, neurotoxic Produce C3 complement A2 Anti-inflammatory, neuroprotective
82
A1 reactive astrocytes
Identified in brains of AD patients Make up large proportion of astrocytes in human AD involved in progression and possibly initiation of disease

Protein Folding and Misfolding in Disease (8 decks)

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