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Biochem Soc Trans. 2005 Apr;33(Pt 2):335-8.

Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein.

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  • 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


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.

[PubMed - indexed for MEDLINE]
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