title: Regulation of amyloid-β production by the prion protein.
abstract: Alzheimer disease (AD) is characterized by the amyloidogenic processing of the amyloid precursor protein (APP), culminating in the accumulation of amyloid-β peptides in the brain. The enzymatic action of the β-secretase, BACE1 is the rate-limiting step in this amyloidogenic processing of APP. BACE1 cleavage of wild-type APP (APPWT) is inhibited by the cellular prion protein (PrP (C) ). Our recent study has revealed the molecular and cellular mechanisms behind this observation by showing that PrP (C)  directly interacts with the pro-domain of BACE1 in the trans-Golgi network (TGN), decreasing the amount of BACE1 at the cell surface and in endosomes where it cleaves APPWT, while increasing BACE1 in the TGN where it preferentially cleaves APP with the Swedish mutation (APPSwe). PrP (C)  deletion in transgenic mice expressing the Swedish and Indiana familial mutations (APPSwe,Ind) failed to affect amyloid-β accumulation, which is explained by the differential subcellular sites of action of BACE1 toward APPWT and APPSwe. This, together with our observation that PrP (C)  is reduced in sporadic but not familial AD brain, suggests that PrP (C)  plays a key protective role against sporadic AD. It also highlights the need for an APPWT transgenic mouse model to understand the molecular and cellular mechanisms underlying sporadic AD.
authors.affiliation: Faculty of Biological Sciences, Institute of Molecular and Cellular Biology, University of Leeds, Leeds, UK.
authors.forename: Heledd H
authors.initials: HH
authors.lastname: Griffiths
authors.forename: Isobel J
authors.initials: IJ
authors.lastname: Whitehouse
authors.forename: Nigel M
authors.initials: NM
authors.lastname: Hooper
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D006801:Humans; D051379:Mice; D018621:PrPC Proteins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D018621:PrPC Proteins; D053829:Amyloid Precursor Protein Secretases