Neurodegenerative Disease Flashcards
1
Q
Hallmarks of Ageing
A
- genomic instability
- telomere attrition
- epigenetic alteration
- loss of proteostasis
- mitochondrial dsyfunction
- stem cell exhaustion
- cellular senescence
- increase in disorder
- electrical parameters decline in the nervous system
2
Q
Healthy Ageing vs Dementia
A
- in healthy ageing there is little or no neuronal loss but synaptic function changes
- dementia is pathological ageing and neurological death
3
Q
Dementia
A
- progressive loss of cognitive and intellectual functions without impairment of consciousness
- caused by structural brain disease
- AD is a type of dementia
4
Q
Alzheimers
A
- occurs with age
- leads to neuron death and failure of all brain systems
- degeneration of fundamental circuits
- myelin attacking, synapses dissolving, loss of brain volume
5
Q
AD Discovery
A
- Alois Alzheimer
- sectioned a patients brain with symptoms of AD and stained with dyes
- found plaques and tangles in the brain
- ‘strange disease of the cerebral cortex’
6
Q
Disease Pathology
A
- neuronal loss
- synaptic damage
- amyloid plaques: precipitate of fat/cholesterol/amyloid
- neurofibrillary tangles: helix of protein
- not known which is first or how they’re related
- can occur together or singly in types of dementia
- Increased AB production facilitates neurofibrillary tangle formation
o Tangles more present in mice with mutant APP
- Removing tau gene from mice alleviates symptoms of APP overexpression
o Some symptoms caused by AB may be mediated by dysregulation of tau
7
Q
Amyloid Plaques
A
- extracellular
- formed of B-amyloid peptide and APOE
- overproduction of B amyloid is involved in mutation
- start in hippocampus
8
Q
Neurofibrillary Tangles
A
- intracellular (inside cells)
- paired helical filaments
- major component is the protein tau (hyperphosphorylated)
9
Q
Familial AD mutations
A
- cause early onset AD with autosomal-dominant mutation
- 3 genes: APP, PS1, PS2 (amyloid precursor protein and presenilin protein)
- also APOE4 allele: strongeset genetic risk factor for late onset AD
- TREM2 allele is also a risk factor
10
Q
Presenilin
A
- proteases processing B-amyloid protein
- control rate of production of amyloid
11
Q
Formation of AB Peptide
A
- B secretase cleaves APP
- y secretase (PS) cleaves APP
- assembly of AB into fibrils
- a secretease can also cleave
- cleavage in the membrane is a biochemical challenge
- proteases provide special environment to get water into the membrane via a passage and cleave the peptide bond
- lateral movement of the substrate in between the TM domains 6/7 and cleavage
12
Q
Amyloid Precursor Protein
A
- no known function
- no effect in knockout mice
- overproduction = disease
- found on the surface of all neurons cell body
- cleavage releases fragments and one fragment is amyloid B peptide
- AB is soluble but close to the crystal state so easily forms assemblies (seed) that can build into a plaque
- happens constantly but older people have more
- reach a clinical threshold of plaques that is toxic to system (toxicity not understood)
- overproduction of deposited proteins leads to disease
13
Q
Amyloid B
A
- cleavage by B secretase generates N terminus and intramembranous cleavage by y secretase gives C terminus
- a secretase cleavage precludes AB formation
- AB is usually soluble and cleared from the brain constantly
- duplication of the APP gene and missense mutations in the APP gene cause inherited AD
- failure of clearance can also cause disease
eg. missense mutation speeding up AP production - not clear why AB is toxic to neurons/their function (some have AB without disease)
14
Q
What is amyloid?
A
- amyloid state: elongated fibers with spines consisting of many stranded B sheets
- amyloid fibers are unbranched usually extracellular and found in vivo
- insoluble: 2 antiparallel B sheets with cross B fiber diffraction pattern
15
Q
Tau
A
- microtubule associated protein (MAP)
- no confirmed function
- expressed in all neurons
- IDP with alternative splicing at N terminal exons and microtubule repeat domains
- domains bind different molecules suggesting a central role in signaling pathways and cytoskeletal organisation
- hyperphosphorylation of tay leads to microtubule destruction
- abundant neurofibrillary tangles and neurophil threads comprised of pathological tau
16
Q
Tau Effects
A
- in a disease neuron there is a loss of Tau binding with microtubule dissociation
- tau is sequestered in tangles
- neuronal transport loss
- new biochemical profile
17
Q
Tau Mutations
A
- there is a sequence of amino acids in the tau gene which when mutated slightly increase the possibility of phos.
- overproduction of hyperphos. tau triggers pathology
18
Q
Tau Structures
A
- paired helical filament of tau protein
- filaments make up protein inclusions
- ind. tau proteins form C shapes stacking together to form filaments with antiparallel B sheets
- twisting filaments of stacked hyperphos. Tau layers
- core has C structures with antiparallel sheets surrounded by fuzzy coats : core is pathological
19
Q
GWAS for AD
A
- most cases of AD have no familial mutation
- GWAS showed APOE gene variations (cholesterol binding protein) was a risk factor
20
Q
APOE
A
- 4 versions of the APOE allele
- unknown function
- blood soluble
- somehow gets into the brain and forms deposits around plaques
- specific aa polymorphisms
- if you are homozygotic for 4 version increases risk
eg. only 20% of 4/4 carriers are unaffected at 75
