Prion Vignette and Alzheimers Flashcards
which is soluble in mild detergent PrPc or PrPsc?
PrPc
how are AB40 and AB42 formed
cleavage by beta secretase followed by gamma secretase
Favored secretase pathway
alpha secretase followed by gamma secretase
where do most AD cases come from?
95% are 65+
Prion Strains
characteristic features that are variable: incubation time in host, clinical signs, distribution of protease resistance PrP in brain. these are stable on serial propagation and posses certian bio-chemcial properties
Role of APP in AD
APP is on chromosome 21 mutation in APP area lead to early onset AD trisomy 21 with 3 copies of APP leads to earlier development of AD
Where does gamma secretase makes its cleave?
Transmembrane region 700-723
what is early age onselt
5-6% of AD
Apolipoprotein E 4
key role in amyloid processing and clearance if you have ApE4, you have more amyloid plaques and AD increases risk by 2 fold, decrease time of onset
Inherited Prion
10% of cases familial strains that lead to early onset CJD, Gerstmann-Straussler Syndrome, Fatal familial insomnia
Apolipoprotein E 4
key role in amyloid processing and clearance if you have ApE4, you have more amyloid plaques and AD increases risk by 2 fold, decrease time of onset
Favored secretase pathway
alpha secretase followed by gamma secretase
Inherited Prion
10% of cases familial strains that lead to early onset CJD, Gerstmann-Straussler Syndrome, Fatal familial insomnia
Presenilin 1
on Chromosome 14 missense mutation that alters single amino acid may be the gamma secretase itself increased production of Beta amyloid protein 42
which is soluble in mild detergent PrPc or PrPsc?
PrPc
Tau
protein that leads to fibrillary tangles inside the cell
how do we increas AB42 clerance?
choleserol or statins
Structural differences in PrPc and PrPsc?
PrPc is alpha helical PrPsc is beta sheets that are hydrophobic and clump
Role of APP in AD
APP is on chromosome 21 mutation in APP area lead to early onset AD trisomy 21 with 3 copies of APP leads to earlier development of AD
Infectious
Decrease inflammatory response of AD
NSAIDS, steriods
what is early age onselt
5-6% of AD
where do AB42 come from?
beta secretase cleavage followed by gamma secretase action on APP
PrPc vs PrPsc
PrPc is the healthy prion protein in all animals PrPsc is the unhealthy prion protein only in diseased animals PrPc is soluble in mild detergent, sensitive to digestion, alpha helix, unstructured N terminis, little beta sheets, globulr 3°, 4° mono oligo-meric PrPsc: not soluble, digestion resistant core, made mostly of beta sheets and are hydrophobic and clump in lesions, 3° structure unknown; 4° is beta sheet linked aggregates. both have identical covalent structure
How do we decrease AB42 toxicity
decrease oligimerization, protect mitochondira
what is sensitive to digestion? PrPc or PrPsc?
PrPc
where do AB42 come from?
beta secretase cleavage followed by gamma secretase action on APP
Tau
protein that leads to fibrillary tangles inside the cell
where do most AD cases come from?
95% are 65+
Structural differences in PrPc and PrPsc?
PrPc is alpha helical PrPsc is beta sheets that are hydrophobic and clump
Presenilin 2 mutaion
on chromosome 1 increase BA42
what is sensitive to digestion? PrPc or PrPsc?
PrPc
relationship between BSE and vCJD
BSE is mad cow disease and vCJD is strain of prion disease that originated in cow and through dietary ingestion lead to vCJD in humans
Sporadic Prion
90% of cases due to mis-folding that infects rest of prions CJD
Beta-Amyloid 42 plaque
incorrectly cleaved protein that forms from A-42 insoluble plaques formed extracellularly
how is APP cleaved?
alpha secretase or Beta secretase transmembrane cleavage by gamma secretase
Prion Strains
characteristic features that are variable: incubation time in host, clinical signs, distribution of protease resistance PrP in brain. these are stable on serial propagation and posses certian bio-chemcial properties
decrease damage to synapses/neurons
memantine
what decreases AB
Iclanders have a mutation near beta cleavage site 40% less AB and decreased risk of AD
Beta secretase knockout
mice are okay, so we are looking at selective beta secretase inhibitors
problem with alzheimers drugs?
they target too low down on the activation pathway. We need to target it before the AB42 starts to accumulate in the brain and symptoms begin developing
how is APP cleaved?
alpha secretase or Beta secretase transmembrane cleavage by gamma secretase
Infectious
What types of prion disease are there?
Sporadic, inherited, infectious
how do we need to decrease AB42 production
modulate secretase activity
PrPc vs PrPsc
PrPc is the healthy prion protein in all animals PrPsc is the unhealthy prion protein only in diseased animals PrPc is soluble in mild detergent, sensitive to digestion, alpha helix, unstructured N terminis, little beta sheets, globulr 3°, 4° mono oligo-meric PrPsc: not soluble, digestion resistant core, made mostly of beta sheets and are hydrophobic and clump in lesions, 3° structure unknown; 4° is beta sheet linked aggregates. both have identical covalent structure
Presenilin 2 mutaion
on chromosome 1 increase BA42
What types of prion disease are there?
Sporadic, inherited, infectious
Beta-Amyloid 42 plaque
incorrectly cleaved protein that forms from A-42 insoluble plaques formed extracellularly
Presenilin 1
on Chromosome 14 missense mutation that alters single amino acid may be the gamma secretase itself increased production of Beta amyloid protein 42
APP
B-amyloid precursor protein large ubiqutiously procued protein in mammalian cells transmembrane protein that is processed by several enzymatic cleavages coded on chromosome 21
APP
B-amyloid precursor protein large ubiqutiously procued protein in mammalian cells transmembrane protein that is processed by several enzymatic cleavages coded on chromosome 21
relationship between BSE and vCJD
BSE is mad cow disease and vCJD is strain of prion disease that originated in cow and through dietary ingestion lead to vCJD in humans
how are AB40 and AB42 formed
cleavage by beta secretase followed by gamma secretase
Gamma secretase knockout
knock out model is lethal seek to modulate activity
Sporadic Prion
90% of cases due to mis-folding that infects rest of prions CJD
what decreases AB
Iclanders have a mutation near beta cleavage site 40% less AB and decreased risk of AD
