title: Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein.
abstract: In the amyloidogenic pathway, the APP (amyloid precursor protein) is proteolytically processed by the beta- and gamma-secretases to release the Abeta (amyloid-beta) peptide that is neurotoxic and aggregates in the brains of patients suffering from Alzheimer's disease. In the non-amyloidogenic pathway, APP is cleaved by alpha-secretase within the Abeta domain, precluding deposition of intact Abeta peptide. The cellular form of the PrP(C) (prion protein) undergoes reactive oxygen species-mediated beta-cleavage within the copper-binding octapeptide repeats or, alternatively, alpha-cleavage within the central hydrophobic neurotoxic domain. In addition, PrP(C) is shed from the membrane by the action of a zinc metalloprotease. Members of the ADAM (a disintegrin and metalloproteinase) family of zinc metalloproteases, notably ADAM10 and TACE (ADAM17) display alpha-secretase activity towards APP and appear to be responsible for the alpha-cleavage of PrP(C). The amyloidogenic cleavage of APP by the beta- and gamma-secretases appears to occur preferentially in cholesterol-rich lipid rafts, while the conversion of PrP(C) into the infectious form PrP(Sc) also appears to occur in these membrane domains.
authors.affiliation: Proteolysis Research Group, School of Biochemistry and Microbiology, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK. n.m.hooper@leeds.ac.uk
authors.forename: N M
authors.initials: NM
authors.lastname: Hooper
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism*; D011328:Prions / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: D016564:Amyloid beta-Protein Precursor; D011328:Prions; D002784:Cholesterol