Cell Death and Neurodegeneration
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- What is the difference between necrosis and apoptosis?
-
1.in necrosis the plasma membrane is ruptured and the contents of the cell spill out and cause inflammation;
2. necrosis is passive, apoptosis is active - Does the extrinsic apoptotic pathway converge with the intrinsic pathway before or after the level of mitochondria?
- either
- What cleaves essential proteins?
- caspases
- In apoptosis and necrosis, DNA is cleaved into ____ fragments.
- 200 bp
- An example of a death receptor ligand
- Fas
- Fas binding induces...
- receptor trimerization
- example of an initiator caspase
- caspase 8
- example of an effector caspase
- caspase 3
- caspase 3 is recruited in an (active/inactive) state
- inactive
- brief overview of extrinsic pathway
- Fas --> timerization --> FADD --> caspase 8 --> caspase 3 --> cleavage of proteins/DNA
- what are some types of death receptors?
- TNF, Fas, p75 NTR
- Describe the domains of death receptors. What do they do?
-
Extracellular: cysteine rich
Cytoplasmic: death domain
They induce trimerization - Describe the intrinsic apoptotic pathway.
-
stimulus -->
intracellular stress signals -->
disrupts balance of pro to anti apoptotic Bcl-2 family members -->
mitochondrial stress -->
release of cytochrome C into cytosol -->
recruitment of adaptor protein (Apaf1) -->
recruits inactive caspase 9 -->
activates caspase 3 -->
cell death - What are pro-antipoptotic molecules? anti?
-
pro (Bax)
anti (Bcl-2 or Bcl-x) - What is in an apoptosome?
-
cytochrome C
caspase 9
Apaf1
dATP - What is Bcl-2?
- a pro-survival oncogene from B-cell lymphoma
- What are the two pro-apoptosis of the Bcl-2 family?
- Bax and BH3 only
- Describe what happens when the intrinsic and extrinsic pathways converge at before caspase 3?
-
1.activation of caspase 8 can cleave Bid --> tBid
2.tBid binds Bax at mitochondria
3.activates intrinsic pathway - What are caspases?
- cysteine proteases that cleave after aspartate residues
- Initiator caspases
- 2,8,9,10
- Effector caspases
- 3,6,7
- Cytokine activator caspases
- 1,4,5,12
- What are initiator caspases?
- latent monomers activated by their dimerization
- What are effector caspases?
- latent dimers activated by cleavage of their interdomain linker
- ______ _______ _______ are by definition active caspases.
- Cleaved Effector Caspases
- In the aging brain there is an increase/decrease in lysosome fxn.
- decrease
- T/F: a normal cell has autphagy occuring at a low level
- True
- The nucleus of an autophagic cell is ________ and _______
-
hyperchromatic (extremely dense)
fragmented - Characteristics of AD
-
amyloid plaques with dystrophic neurites
neurofibrillary tangles - 5 groups of AD:
-
sporadic late onset
familial late onset
familial early onset
Assoc. w/ down syndrome
Assoc. w/ other neurodegen. disorder (parkinson's) - Macroscopic changes in AD brain:
-
dec brain weight
widening of sulci
narrowing of gyri
dec white matter - What regions are primarly affected in AD?
- hippocampus and cortex
- Primary neurochemical effects:
-
loss of Ach
loss of cholinergic pre-synaptic markers (ex. nicotinic receptors) - Secondary neurochemical effects:
-
loss of GABAergic cortical neruons
loss of 5-HT and adrenergic input to cortex from other areas - Microscopic changes in AD:
-
extracellular amyloid plaques
neurfibrillary tangles
dystrophic neuritis
massive loss of cortical synapses and neurons
inc in undigested lipopigment
inc. in number of autophagosomes - What makes up neurofibrillary tangles?
- hyperphosphorylated tau
- What forms amyloid beta plaques?
- amyloid precursor protein
- How does the APP pathway work normally?
- APP is cleaved by alpha-secretase preventing formation of amyloid beta
- What happens to APP pathway in AD brain?
- APP is cleaved by beta-secretase or gamma-secretase and creates amyloid beta peptide which aggregates to form plaques
- Hypothetical Amyloid Cascade model of AD
-
1.APP cleaved by beta and gamma secretases to form AB
2.AB fibrillates and forms plaques
3.AB can activate microglia causing an inflamm. response around plaque
4.activated microglia cause cell death response
5. AB reacts with neuron causing dystrophic neuritis - In AD there is extensive ______ ______ and _____ _____.
-
neuron death
synapse loss - AD has (acute/chronic) onset and progression.
- chronic