Neurobiology 8 Flashcards
Give examples of the features of ageing.
Genomic instability.
Shortening of telomeres.
Stem cell exhaustion.
Give a definition of healthy ageing.
No specific disease, natural ageing and dying without any debilitating disease. (little or no neuronal loss)
Give a definition of dementia.
Progressive loss of cognitive functions, including memory , without impairment of perception or consciousness.
What disease is the most common form of dementia?
Alzheimer’s disease
In Alzheimer’s, do circuitry responsible for making neuromodulators degenerate?
Yes - lack dopamine means addictive means addictive behaviours are lost (reduced urge to smoke).
What does the brain of Alzheimer’s disease look like?
Brain appears shrivelled - substantial loss of brain volume.
Why is there widespread neuronal death in AD brain?
Because most neurons are post-mitotic so will not regenerate.
What happens to the remaining (alive) neurons in the brain of an AD patient?
They have degenerated myelin and axons - so slower conduction.
What can form amyloid fibrils?
Partially folded intermediates/degraded fragments.
Can all types of proteins form amyloids?
Yes.
What does the fact that all proteins can form amyloid fibrils suggest?
That amyloid fibrils are the real thermodynamic minimum in folding.
What % of people have Alzheimers +65 years?
10%
What % of people have Alzheimers +85years?
50%
What happens to brain tissue that contain amyloid plaques?
They form neurofibrillary tangles.
Where do you find amyloid plaques?
Found between neurons - extracellular.
Where do you find neurofibrillary tangles?
Found between axons and cell bodies (intracellular).
What do amyloid plaques consist of?
Beta-amyloid peptides
Can also contain ApoE cholesterol binding protein
What are neurofibrillary tangles made of?
Formed of paired helical filaments - main component is hyperphosphorylated Tau protein.
Which protein is Amyloid Beta peptide derived from?
Amyloid beta precursor protein (AbetaPP) - it undergoes proteolysis to form this.
What is the pathway of amyloid fibril formations?
Native –> amyloidgenic intermediate –> oligomers –> protofibrils –> amyloid fibrils.
What is the most toxic species in pathway?
Oligomers - not structurally defined.
Are amyloid fibrils resistant to detergents/unfolding agents?
Yes.
What do oligomers have the ability to do?
Penetrate cellular membranes.
What secondary structure are amyloids made of?
Extended beta sheets.
What is distance between beta strands in amyloids? and what is distance between beta sheets in amyloids?
4.7A and 10.7A
‘Some people develop AD at a younger age (30-40)’ why does this happen?
Genetic predisposition - 1%
What 3 mutations are associated with a genetic predisposition for early onset AD?
Mutations in:
- amyloid precursor protein.
- PS1 - presenilin 1
- PS2 - presenilin 2
What is the strongest genetic risk factor for late on set AD?
ApoE4 allele.
What are the 2 possible SNPs within the ApoE4 result in?
3 possible alleles:
E2, E3, E4.
What 3 proteases are responsible for cleaving APP?
Alpha-secretase, beta secretase and gamma secretase.
What part of APP does gamma secretase cleave?
The N terminal region.
What region does gamma secretase cleave in APP?
The C terminal region.
Where is presenilin 1 found?
It is one of the 4 core proteins in the gamma secretase complex.
Give examples of gamma secretase substrates which result in cell signalling.
Notch, ErbB4, N-cadherin and E-cadherin.
What can the soluble form of beta amyloid cause?
Can cause poisoning of LTP - could possibly account for memory loss.
What is normal function of amyloids?
May have a function in the storage of peptide hormones - peptide and protein hormones stored in amyloid-like beta sheet rich conformation to save space in vesicles.
What is the tau protein?
Tau is an intrinsically disordered protein.
What does tau bind to?
Selectively binds to microtubules and also has other domains that bind different molecules - role in signalling.
What happens when there are mutations in the tau gene?
Microtubules degenerate and tau deposits form.
Formation of neurofibrillary tangles.
Does tau tend to be phosphorylated or not?
Yes
What sort of structure does hyperphosphorylated tau assume?
An amyloid like structure.
Where are tau filaments found in the brain of an AD patient?
Spread from the hippocampus through the cortex.
What are the normal functions of tau?
Main function: regulates microtubules in axonal transport.
Also involved in the formation of dendritic spines and in maintenance of DNA.
What happens if tau cannot regulate microtubules in axonal transport?
Neuronal function degenerates.
Give examples of some treatments for Alzheimer’s disease?
Secretase inhibitors (beta/gamma) - inhibits Beta amyloid production. Phosphorylation inhibitors - reduce tau hyperphosphorylation.
What is the problem with inhibiting secretases and kinases to treat AD?
They have other targets within the body so produce bad side effects.
What is the second most common neurodegenerative disease?
Parkinson’s disease.
List some symptoms of Parkinson’s disease.
Cannot plan movements or thought.
Tremors.
Dementia (late stage).
What causes PD?
Lewy bodies formed from aggregation of alpha synuclein.
What percentage of cases does familial PD account for?
15%
What mutations are associated with familial PD?
Alpha-synuclein gene (usually early on set).
Leucine rich repeat kinase 2 gene (late onset)
What gene is increases the risk of getting PD (does not cause it)?
Glucocerebrosidase (GBA) gene.
What is juvenile onset PD?
A rare form of PD occuring in those under 20.
What is juvenile onset PD thought to be caused by?
Defects in mitochondrial damage repair.
E3 ubiquitin ligase (Parkin).
Mitochondrial protein kinase (PINK1).
Give examples of mutations in the Alpha synuclein gene (SNCA).
Increased gene dosage, due to gene duplication/triplication - over-expression of protein.
Missense mutations.
Can alpha synuclein be converted to a toxic structure containing beta sheets?
Yes.
What does shaking a-synuclein at a specific temperature cause?
Conversion to the toxic beta sheet form.
Why do non-motor symptoms appear first?
Deposits of a-synuclein begin in the gut and spread to the brain stem.
Where do the aSN deposits spread to from the brain stem?
The hypothalamus (involved in sleep)
Which neurons does aSN kill?
Dopmaine neurons.
How could PD be treated?
Dopamine neuron transplant - using stem cells.
Why is a dopamine neuron transplant not very efficient for PD?
The lewy bodies spread into the transplant neurons.
What the size of Prion protein and what is it bound to?
209aa and membrane bound.
Is prion protein self propagating and what does this mean?
Yes - can convert normal cellular prion protein to scrapie protein.
