NDLI: Prion Protein Interacts with BACE1 Protein and Differentially Regulates Its Activity toward Wild Type and Swedish Mutant Amyloid Precursor Protein*

Content Provider	PubMed Central
Author	Griffiths, Heledd H. Whitehouse, Isobel J. Baybutt, Herbert Brown, Debbie Kellett, Katherine A. B. Jackson, Carolyn D. Turner, Anthony J. Piccardo, Pedro Manson, Jean C. Hooper, Nigel M.
Copyright Year	2011
Abstract	In Alzheimer disease amyloid-β (Aβ) peptides derived from the amyloid precursor protein (APP) accumulate in the brain. Cleavage of APP by the β-secretase BACE1 is the rate-limiting step in the production of Aβ. We have reported previously that the cellular prion protein (PrPC) inhibited the action of BACE1 toward human wild type APP (APPWT) in cellular models and that the levels of endogenous murine Aβ were significantly increased in PrPC-null mouse brain. Here we investigated the molecular and cellular mechanisms underlying this observation. PrPC interacted directly with the prodomain of the immature Golgi-localized form of BACE1. This interaction decreased BACE1 at the cell surface and in endosomes where it preferentially cleaves APPWT but increased it in the Golgi where it preferentially cleaves APP with the Swedish mutation (APPSwe). In transgenic mice expressing human APP with the Swedish and Indiana familial mutations (APPSwe,Ind), PrPC deletion had no influence on APP proteolytic processing, Aβ plaque deposition, or levels of soluble Aβ or Aβ oligomers. In cells, although PrPC inhibited the action of BACE1 on APPWT, it did not inhibit BACE1 activity toward APPSwe. The differential subcellular location of the BACE1 cleavage of APPSwe relative to APPWT provides an explanation for the failure of PrPC deletion to affect Aβ accumulation in APPSwe,Ind mice. Thus, although PrPC exerts no control on cleavage of APPSwe by BACE1, it has a profound influence on the cleavage of APPWT, suggesting that PrPC may be a key protective player against sporadic Alzheimer disease.
Related Links	http://dx.doi.org/10.1074/jbc.M111.278556
Starting Page	33489
File Format	PDF
ISSN	1083351X
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	38
Volume Number	286
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2011-09-23
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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