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MEDICAL BIO > WEEK 10 - neurodegenerative diseases > Flashcards

WEEK 10 - neurodegenerative diseases Flashcards

1
Q

neurodegenerative diseases
fundamental research

A

brain disorders
–> gene identification
–> animal models
–> pathogenesis studies
–> basic neurobiology
–> candidate pathways for therapeutic intervention
–> preclinical trials
–> clinical trials
–> successful therapies

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2
Q

Alzheimer’s disease
overview

A

sporadic or familial AD (familial rare, 2%)

affects 1:20 people over 65 and 50% over 85
it is the most common neurodegenerative disease

Familial AD is early onset: ~in 40s-50s

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3
Q

Alzheimer’s disease
pathology

A

loss of synaptic connections, dendrites and axon
neurons die: BRAIN ATROPHY

Starts as a problem of memory (acquisition of new memory as it requires the hippocampus)

loss of memory and spatial orientation, followed by loss of cognitive ability (reasoning and language)

affects firstly the hippocampus the extends beyond
the hippocampus is required fro forming new memories and for spatial navigation

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4
Q

Alzheimer’s disease
inherited?

A

Rarely inherited
- Lots of other factors (not due to inheritance) contribute
- Could be more genetic contribution than we realise
Just haven’t found it yet

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5
Q

Alzheimer’s disease
pathological features

A

amyloid plaques (extracellular)
- formed of AB-amyloid

neurofibrillary tangles (intracellular)
- formed of hyper-phospho-Tau

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6
Q

Alzheimer’s disease
pathological features: where

A

both present in normal old people but their prevalence in hippocampus, amygdala and cortex increases with AD

amygdala has a key role in processing emotions, memory and learning

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7
Q

Alzheimer’s disease
molecular mechanism of AB-amyloid formation

A

AB-amyloid is a product of APP cleavage
normal function of APP unknown, possibly for normal memory
AB fragments prone to aggregation

to produce AB:
- APP needs to be cleaved in two places
–> B-secretase and y-secretase

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8
Q

Alzheimer’s disease
molecular mechanism of AB-amyloid formation:
a-secretase

A

a-secretase cleavage prevents formation of AB fragments

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9
Q

Alzheimer’s disease
molecular mechanism of AB-amyloid formation:
y-secretase

A

produces prominently AB40 and AB42

cleaves many proteins

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10
Q

Alzheimer’s disease
molecular mechanism of AB-amyloid formation:
familial AD

A

predominantly mutation in APP near site of y-secretase, which increases production of AB42

Inherited characterised by mutations in the secretase gene
- That lead to more ABeta

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11
Q

Alzheimer’s disease
molecular mechanism of AB-amyloid formation:
protective mutation

A

near B-secretase site

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12
Q

Alzheimer’s disease
familial AD is caused by…

A

mutations in APP and presenilins

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13
Q

Alzheimer’s disease
familial AD is caused by mutations in APP and presenilins

A

mutations in APP and presenilin increase AB42 production

presenilins are part of the y-secretase complex

down syndrome patients have an extra copy of APP and develop AD in their 40s-50s

AB42 oligomers prevent LTP, cause synaptic loss and neuronal death

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14
Q

Alzheimer’s disease
familial AD is caused by mutations in APP and presenilins:
mouse models

A

Mouse models
Mice that develop alz
Mutations that favour production of Abeta
And then develop amyloid plaques

Effect on long term potentiation
(in mice)
Electrophysiological manifestation of learning

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15
Q

Alzheimer’s disease
ApoE is an AD…

A

susceptibility locus

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16
Q

Alzheimer’s disease
ApoE

A

mutations in APP and PSN = 2% of cases only

ApoE: component of high-density lipoproteins, involved in lipid transport and metabolism
–> Binds AB
–> Pushes forward the development of alz

40% of AD patients have the ApoE-e4 allele (instead of e3)

the ApoE-e2 allele is PROTECTIVE

mechanisms are unknown

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17
Q

Alzheimer’s disease
ApoE
why are lipids important

A

Neurons are complex and large
Need a lot of lipids to keep membranes in place
If have problems with lipids the neuronal membranes are going to degrade quicker (than normal) leading the alz

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18
Q

Alzheimer’s disease
microgila dysfunction leads to…

A

defective clearance of AB-amyloid deposits

need brian proteiostasis (protein balance)

Microglia function is imperative
Dysfunction microglia can cause brain disease

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19
Q

Alzheimer’s disease
normal microglia action

A

clear up excess protein maintaining normal proteostasis

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20
Q

Alzheimer’s disease
treatment of;
amyloid-B plaques

A

immunisation
small molecule based-therapy

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21
Q

Alzheimer’s disease
treatment of;
neurofibrillary tangles

A

immunisation
small molecular based therapy

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22
Q

Alzheimer’s disease
treatment of;
inflammation

A

immunisation
small molecular based therapy

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23
Q

Alzheimer’s disease
treatment of;
network disruption

A

small molecular based therapy
deep brain stimulation

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24
Q

Alzheimer’s disease
treatment of;
cognitive dysfunction

A

cognitive training
E.g. keeping brain active, sport, instrument
- To keep the parts of the brain that are working active

lifestyle changes

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25
Alzheimer's disease treatment: best strategy
early detection
26
Alzheimer's disease treatment: drugs to reduce AB toxicity
inhibit B-secretase or y-secretase increase clearance neutralise
27
Alzheimer's disease treatment: problem with drugs to reduce AB toxicity
secondary effects e.g. y-secretase cleaves many other proteins Many other functions If prevent function of this What are the other consequences elsewhere in the brain
28
Alzheimer's disease treatment: biomarkers
positron emission tomography (PET) to detect AB deposits before symptom onset using Pittsburg compound B (PIB) which binds AB
29
Alzheimer's disease treatment: network level treatment
trans-cranial magnetic stimulation deep brain stimulation
30
Alzheimer's disease from lab to clinic
interfere with AB production by inhibiting B-secretase --> identify a chemical compound or an antibody that inhibits B-secretase --> use wildtype animals to optimize for accessibility across the blood-brain barrier, safety, and pharmacokinetics; use animal AD models to test therapeutic effects on neuropathology, physiology and behaviour --> safety and tolerability? effects on AB? deposition? effects on cognitive function?
31
Prion diseases: caused by
propagation of protein-induced protein conformational change
32
Prion diseases:
sponge like-holes in the brain - scrapie: infects sheep and goats, mad cows' disease --> contact with dead animals - kuru in human cannibals - creutz-jakob disease (CJD): no infection protein more prone
33
Prion diseases: in mice
In mice If mutant does not have effective protein no disease However if have protein will have disease Demonstrating that there is a knock on effect from induced conformational change in proteins Prp-/-KO mice are resistant to infection with Prp^Sc
34
what underlies many neurodegenerative diseases
aggregation is misfolded proteins
35
aggregation of proteins and neurodegenerative diseases: Huntington's disease
Huntington disease (HD): depression, mood swings, abnormal movement, cognitive deficits, death after 10-20 years expansion of CAG (poly-glutamine = polyQ) at N terminus of Huntington protein aggregates = inclusion bodies in nucleus, cytoplasm, axons, etc
36
parkinson's disease affects the
dopaminergic system
37
parkinson's disease:
tremor, rigidity, problems walking death of dopaminergic neurons of the substantia nigra dopamine regulates movement dysregulation of dopamine-ACh balance
38
Substantia nigra
Substantia nigra is an area of the brain with the highest concentration of dopaminergic neurons in the brain
39
Parkinson's disease onset
late onset, no clear inheritance pattern, most sporadic inheritance There isnt one? Havent found one yet?
40
Parkinson's disease familial PD
only 1% of cases mutation in a-synuclein
41
Parkinson's disease pathology
lewy bodies: intracellular inclusion of a-synuclein over production of a-synuclein is sufficient to cause lewy bodies and PD a-syniclein aggregates start in brain stem and substantia nigra then spread throughout cortex - might be transported across neurons - The aggregates interfere with neuronal function spread does not occur when a-synuclein KO mice are injected with a-synuclein: protein behaviour like prions defective proteostasis
42
what underlies PD
aggregates of a-syncleinu accumulation of a-synuclein block vesicle trafficking, protein clearance and degradation and mitophagy (i.e. clearance of defective mitochondria) defective mitochondria build up causes oxidative stress (exacerbates the damage)
43
Parkinsons disease vesicle release and mitochondrial disfunction
normal function of a-synuclein: presynaptic, to modulate synaptic vesicle release in PD, a-synuclein accumulates, interfering with the priming of vesicles, decreasing the size of the releasable pool
44
Parkinsons disease 10-15% familial PD can be caused by recessive mutations in:
Pink1: mitochondria associate kinase Parkin: ubiquitin-proteasome system for protein degradation. Pink and Park regulate mitochondrial function, movement along microtubules and removal of damaged mitochondria DNAJC6, GAK: endocytic pathway
45
Parkinson disease: prion hypothesis
prion behaviour of a-synuclein: - a-synuclein can be secreted and endocytosed - spreading requires a-synuclein: does not occur in a-synculein KO mice microglia and inflammation: could be a good or bad thing - debris clearance function of microglia might get saturated with a-synuclein - coule provoke microglial activation
46
why are dopaminergic neurons sensitive to a-synuclein
DA neurons in humans are particularly exuberant: challenge for vesicle trafficking one human DA neuron can have 1 million axon terminals
47
neural circuit underlying PD
see slide basically in normal: Consequence of the direct and indirect pathway Allows movement in PD patient: Consequence of direct and indirect pathway inhibits movement
48
parkinsons disease: treatment:
boost dopamine levels target the lysosome deep brain stimulation cell replacement therapy
49
parkinsons disease: treatment: boost dopamine levels
administer L-Dopa, as dopamine cannot cross the blood brain barrier only effective for a few years as dopamine neurons keep dying
50
parkinsons disease: treatment: target lysosome
Bcyclodextrins: increase lysosomal function
51
parkinsons disease: treatment: deep brain stimulation
electrode surgically implanted to stimulate neurons in specific nuclei in the STN and GPi can alleviate symptoms of PD when L-Dopa become less effective In most cases shuts down (inhibits) areas in the brain around a particular part of the electrode
52
parkinsons disease: treatment: cell replacement therapy
transplantation of dopamine neurons into the brain
53
parkinsons disease: treatment strategy: challenges of cell replacement therapy
need dopaminergic neuron in large amounts no contamination from other cell types immuno-suppression better use patient stem cells to produce dopaminergic neurons in vitro: iPSCs movement recovery in PD patients with transplanted DA neurons PET scans shows radioactive marker in dopamine neurons: looks normal after transplantation of DA neurons
54
summary neurodegenerative diseases: all neurodegenerative disease share in common the...
formation of protein aggregates
55
summary neurodegenerative diseases: what tends to facilitate aggregate formation
mutant forms of proteins
56
summary neurodegenerative diseases: misfolded protein are
toxic or alter localisation or function of their normal partner proteins - altering protein hemeostasis
57
summary neurodegenerative diseases: abnormal proteins seeds..
conformational changes and cell-to-cell spread
58
summary neurodegenerative diseases: difference diseases affect...
different neuronal types AD starts in hippocampus PD starts in substantia nigra, loss of dopaminergic neurons
59
summary neurodegenerative diseases: the proteins involved are
widely expressed so not known why they affect specific neuronal types maybe interacting proteins determine this
60

MEDICAL BIO (17 decks)

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