Neurodegeneration

Question 1

what is neurodegeneration?

Answer 1

the progressive loss of neuronal structure, function and/or number

Question 2

what is the overview of alzheimer progression?

Answer 2

healthy brain -> mild disease = shrinkage of cerebral cortex, enlargement of vesicles and hippocampal shrinkage –> severe disease= more drastic symptoms = amyloid plaques and disintegrating microtubules

Question 3

what is the pathology of parkinsons?

Answer 3

diminished substantia nigra due to loss of neurons in the midbrain

Question 4

what are 6 risk factors for neurodegeneration?

Answer 4

age
genetics
lifestyle
head-heart
mild trauamtic brain injury
metabolic abberations

Question 5

what are 5 cellular features of alzheimers disease?

Answer 5

amyloid plaques
accumulation of hyper phosphorylated tau protein
neuroinflammation
cell death

Question 6

what are the 4 intracellular features of alzheimers?

Answer 6

intracellular amyloid accumulation
accumulation of hyper phosphorylated tau
mitochondrial dysfunction
oxidative stress

Question 7

what is the pathology of alzheimers at an anatomical level

Answer 7

loss of cells in the cerebral cortex and hippocampus

Question 8

what are three cellular features of parkinsons

Answer 8

accumulation of large bags of proteins= lewy bodies
neuro inflammation
cell death- substantia nigra

Question 9

what are three intracellular features of parkinsons

Answer 9

alpha-synucleic aggregate in cells
mitochondrial dysfunction
oxidative stress and damage

Question 10

what are the 6 stages of protein phosphorylation for neurodegeneration

Answer 10

misfolding
dimers
olgimers
protofibrills
bigger aggregates / amyloid fibres
leading to toxicity neurodegeneration

Question 11

what is tau

Answer 11

a microtubule associated protein

Question 12

what are three advantages of microtubules in axons

Answer 12

neural outgrowth
axonal transport
microtubule dynamics

Question 13

describe tau phosphorylation for physiological process

Answer 13

at sites serine 119/202 and threonine 205

Question 14

what enzymes are thought to phosphorylate tau?

Answer 14

PKA and MARK

Question 15

what happens when tau fillaments form?

Answer 15

no longer associated with microtubules

Question 16

what are the phosphorylation sites in the pre tangles and neurofibrally tangles of AD

Answer 16

serine 62 and threonone 231

serine 442 in neuro tangles

Question 17

what mediates serine 442 phosphorylation in AD

Answer 17

GSK-3beta

Question 18

what is the leading cause of cell death in AD?

Answer 18

non functioning microtubules

Question 19

what is the pathology of tau phosphorylation in AD?

Answer 19

tau filament formaiton
microtubule dysfunction
cell death

Question 20

what does abnormal phosphorylation lead to ?

Answer 20

hyperphosphorylation and a chain reaction

Question 21

What are the two pathways of proteolytic cleavage in AD?

Answer 21

non-amyloidogenic

amyloidogenic

Question 22

what is APP

Answer 22

amyloid precursor pathway

Question 23

what is the normal pathway for non-amyloidogenic pathway in AD?

Answer 23

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)

Question 24

what is the molecule involved in amyloidogenic pathway

Answer 24

soluble APP-beta and it is left in larger chunks when cut up so C99 left in membrane

Question 25

what is C99 left in the membrane in AD, further cleaved by

Answer 25

gamma secretase

Question 26

what produce amyloid beta

Answer 26

abnormalities of proteolytic cleavage of app, cleaved by non-amyloidogenic pathway aggregate in and out of cell

Question 27

what can proteins aggregate by?

Answer 27

hyperphosphorylation

Question 28

what is a mechanism of alpha synucleic aggregation in parkinsons?

Answer 28

protein misfolding | cell under stress due to misfolding

Question 29

describe protein misfolding and parkinsons

Answer 29

need protein not just be long string of AA but fold so it can do its job - misfolded means cannot do job

Question 30

where are proteins folded?

Answer 30

in the ER and cytosol

Question 31

what happens to misfolded proteins?

Answer 31

protein intermediates can go to lysosome or others are broken down by ubiquitations or fold correctly in the cytosol

Question 32

what do misfolded proteins lead to in parkinsons

Answer 32

lewy bodies formation

Question 33

what are ROS

Answer 33

reactive oxygen species which are highly reactive and short lived

Question 34

what causes ROS

Answer 34

form of a free radical - unpaired electron

Question 35

describe ROS interaction with other molecules

Answer 35

interact by donating or recieving an electron to achieve stability

Question 36

what is an oxidative modification

Answer 36

addition of an oxygen molecule to or from a ROS

Question 37

what is oxidative stress

Answer 37

when production of ROS outweighs cells antioxidant defences leading to oxidative damage to nucleotides, proteins, and lipids

Question 38

what is one of the main cellular sources of ROS

Answer 38

mitochondria

Question 39

what is the vicious cycle between ROS and mitochondra

Answer 39

ROS causes damage leading to further production of ROS

Question 40

what are 4 genes associated with PD that affect mitochondria

Answer 40

SNCA Parkin Dj-1 LRRk2

Question 41

what are two molecules associated with mitcohdondrial dysfunction in the early stages of AD

Answer 41

APP or PSn1 mutations

Question 42

what are the 5 stages of microglia activation

Answer 42

``` ramified (r-stage) activation signal transitional (t-stage) motile (m-stage) locomotory (l-stage) ```

Question 43

where can we find more microglia in AD patients

Answer 43

hippocampus and cortex

Question 44

where does stimulus for microglia come from in AD patients?

Answer 44

unknown damage signals- neuron damage activates microglia initiating an immune response

Question 45

describe microglia recruitmeent in PD

Answer 45

activation of death receptors | TNF alpha activates TNFR1 leading to cell death