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

In the amyloidogenic pathway, the APP (amyloid precursor protein) is proteolytically processed by the beta- and y-secretases to release the A beta (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 a-secretase within the A beta domain, precluding deposition of intact A beta peptide. The cellular form of the PrPc (prion protein) undergoes reactive oxygen Species-mediated beta-cleavage within the copper-binding octapeptide repeats or, alternatively, a-cleavage within the central hydrophobic neurotoxic domain. In addition, PrPc 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 a-secretase activity towards APP and appear to be responsible for the a-cleavage of PrPc. The amyloidogenic cleavage of APP by the beta- and y-secretases appears to occur preferentially in cholesterol-rich lipid rafts, while the conversion of PrPc into the infectious form PrPSc also appears to occur in these membrane domains.