Neurodegeneration Flashcards
what is neurodegeneration?
the progressive loss of neuronal structure, function and/or number
what is the overview of alzheimer progression?
healthy brain -> mild disease = shrinkage of cerebral cortex, enlargement of vesicles and hippocampal shrinkage –> severe disease= more drastic symptoms = amyloid plaques and disintegrating microtubules
what is the pathology of parkinsons?
diminished substantia nigra due to loss of neurons in the midbrain
what are 6 risk factors for neurodegeneration?
age genetics lifestyle head-heart mild trauamtic brain injury metabolic abberations
what are 5 cellular features of alzheimers disease?
amyloid plaques
accumulation of hyper phosphorylated tau protein
neuroinflammation
cell death
what are the 4 intracellular features of alzheimers?
intracellular amyloid accumulation
accumulation of hyper phosphorylated tau
mitochondrial dysfunction
oxidative stress
what is the pathology of alzheimers at an anatomical level
loss of cells in the cerebral cortex and hippocampus
what are three cellular features of parkinsons
accumulation of large bags of proteins= lewy bodies
neuro inflammation
cell death- substantia nigra
what are three intracellular features of parkinsons
alpha-synucleic aggregate in cells
mitochondrial dysfunction
oxidative stress and damage
what are the 6 stages of protein phosphorylation for neurodegeneration
misfolding dimers olgimers protofibrills bigger aggregates / amyloid fibres leading to toxicity neurodegeneration
what is tau
a microtubule associated protein
what are three advantages of microtubules in axons
neural outgrowth
axonal transport
microtubule dynamics
describe tau phosphorylation for physiological process
at sites serine 119/202 and threonine 205
what enzymes are thought to phosphorylate tau?
PKA and MARK
what happens when tau fillaments form?
no longer associated with microtubules
what are the phosphorylation sites in the pre tangles and neurofibrally tangles of AD
serine 62 and threonone 231
serine 442 in neuro tangles
what mediates serine 442 phosphorylation in AD
GSK-3beta
what is the leading cause of cell death in AD?
non functioning microtubules
what is the pathology of tau phosphorylation in AD?
tau filament formaiton
microtubule dysfunction
cell death
what does abnormal phosphorylation lead to ?
hyperphosphorylation and a chain reaction
What are the two pathways of proteolytic cleavage in AD?
non-amyloidogenic
amyloidogenic
what is APP
amyloid precursor pathway
what is the normal pathway for non-amyloidogenic pathway in AD?
chooping up soluble APP-alpha via alpha secretase
production of peptide p3
after these cuts- AICD left in membrane (maybe involved in signalling and axonal transport)
what is the molecule involved in amyloidogenic pathway
soluble APP-beta and it is left in larger chunks when cut up so C99 left in membrane
what is C99 left in the membrane in AD, further cleaved by
gamma secretase
what produce amyloid beta
abnormalities of proteolytic cleavage of app, cleaved by non-amyloidogenic pathway
aggregate in and out of cell
what can proteins aggregate by?
hyperphosphorylation
what is a mechanism of alpha synucleic aggregation in parkinsons?
protein misfolding
cell under stress due to misfolding
describe protein misfolding and parkinsons
need protein not just be long string of AA but fold so it can do its job - misfolded means cannot do job
where are proteins folded?
in the ER and cytosol
what happens to misfolded proteins?
protein intermediates can go to lysosome or others are broken down by ubiquitations or fold correctly in the cytosol
what do misfolded proteins lead to in parkinsons
lewy bodies formation
what are ROS
reactive oxygen species which are highly reactive and short lived
what causes ROS
form of a free radical - unpaired electron
describe ROS interaction with other molecules
interact by donating or recieving an electron to achieve stability
what is an oxidative modification
addition of an oxygen molecule to or from a ROS
what is oxidative stress
when production of ROS outweighs cells antioxidant defences leading to oxidative damage to nucleotides, proteins, and lipids
what is one of the main cellular sources of ROS
mitochondria
what is the vicious cycle between ROS and mitochondra
ROS causes damage leading to further production of ROS
what are 4 genes associated with PD that affect mitochondria
SNCA
Parkin
Dj-1
LRRk2
what are two molecules associated with mitcohdondrial dysfunction in the early stages of AD
APP or PSn1 mutations
what are the 5 stages of microglia activation
ramified (r-stage) activation signal transitional (t-stage) motile (m-stage) locomotory (l-stage)
where can we find more microglia in AD patients
hippocampus and cortex
where does stimulus for microglia come from in AD patients?
unknown damage signals- neuron damage activates microglia initiating an immune response
describe microglia recruitmeent in PD
activation of death receptors
TNF alpha activates TNFR1 leading to cell death
