clinical vingettes Flashcards
Amyloids
insoluble fibrous protein aggregates sharing specific structural traits. They arise from at least 18 inappropriately folded versions of proteins and polypeptides present naturally in the body.
Aβ42
the most amyloidogenic form of the peptide.
b-Amyloid precursor protein (APP)
b-Amyloid precursor protein (APP) is a large ubiquitously produced protein in mammalian cells. APP is transmembrane protein that is processed by several possible enzymatic cleavages. Extracellular cleavage occurs either by a–secretase or b- secretase (BACE, b-amyloid cleaving enzyme).Transmembrane cleavage by g– secretase
Where does (Aβ42) come from?
b- secretase followed by g– secretase action on b-amyloid precursor protein
b-amyloid precursor protein (b-APP) processing
favored pathway is a- secretase followed by g– secretase. Cleavage of APP by b- secretase followed by g– secretase yields Aβ40 and Aβ42
Evidence that β-Amyloid peptide has pivotal role in Alzheimer’s Disease
APP is coded for on chromosome 21. Mutations APP area chromosome 21 is correlated with early onset AD. Trisomy 21 creates 3 copies APP gene and is correlated with AD by midlife. All known mutations assoc with increased rates of AD is correlated with an increase Aβ either by increased production or decreased clearance Aβ.
ApoE e4
A variant of apolipoprotein E, which plays a role in amyloid processing and clearance. This variant increases amyloid deposition and increases rates of AD
Presenilin 1
may be the γ-secretase itself. A missense mutation was found in 50% of AD cases
Which of mutation acts by increasing production of all b-amyloid proteins?
b-amyloid precursor protein mutations (chromosome 21)
prion
are proteins that access self-templating amyloid forms, which confer phenotypic changes that can spread from individual to individual within or between species. This ability to access self-templating amyloid forms is not, however, unique to prion proteins. Several fatal neurodegenerative diseases are also associated with the accumulation of self-templating amyloid forms of specific proteins. For example, b-amyloid (Ab) and tau misfold in Alzheimer’s disease (AD)
Potential Interventions to Prevent/Delay AD
Decrease production Ab42 : modulate secretase activity; increase Ab42 clearance: cholesterol/statins, vax; decrease Ab42 toxicity: decrease oligimerization, protect mitochon; decrease oxidation injury: chelate divalent metals; decrease inflammatory response: NSAIDs; decrease damage to synapses/neurons: memantine; Compensate for neuronal dysfunction: donepezil
infectious prion
vCJD, Kuru
genetic prion disease
Familial CJD, Gerstmann-Straussler syndrome (GSS), Fatal familial insomnia (FFI)
Sporadic prion disease
Creutzfeldt-Jakob disease (CJD)
why do prions have partial protease resistance?
tight agrigate-> protease can not gain access for its function (niether can detergent)
