Published online before print June 15, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0609621104
Neuroscience
Cellular prion protein regulates -secretase cleavage of the Alzheimer's amyloid precursor protein
( lipid raft | proteolysis | scrapie | glycosaminoglycan )
Edward T. Parkin *, Nicole T. Watt *, Ishrut Hussain , Elizabeth A. Eckman ¶, Christopher B. Eckman ¶, Jean C. Manson ||, Herbert N. Baybutt ||, Anthony J. Turner *, and Nigel M. Hooper ***
*Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, and Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, United Kingdom; Neurodegeneration Research, Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Limited, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom; ¶Mayo Clinic, Jacksonville, FL 32224; and ||Roslin Institute, Neuropathogenesis Unit, Edinburgh EH9 3JF, United Kingdom
Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved May 10, 2007 (received for review October 30, 2006)
Proteolytic processing of the amyloid precursor protein (APP) by -secretase, -site APP cleaving enzyme (BACE1), is the initial step in the production of the amyloid (A) peptide, which is involved in the pathogenesis of Alzheimer's disease. The normal cellular function of the prion protein (PrPC), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans, remains enigmatic. Because both APP and PrPC are subject to proteolytic processing by the same zinc metalloproteases, we tested the involvement of PrPC in the proteolytic processing of APP. Cellular overexpression of PrPC inhibited the -secretase cleavage of APP and reduced A formation. Conversely, depletion of PrPC in mouse N2a cells by siRNA led to an increase in A peptides secreted into the medium. In the brains of PrP knockout mice and in the brains from two strains of scrapie-infected mice, A levels were significantly increased. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases failed to inhibit the -secretase cleavage of APP. Using constructs of PrP, we show that this regulatory effect of PrPC on the -secretase cleavage of APP required the localization of PrPC to cholesterol-rich lipid rafts and was mediated by the N-terminal polybasic region of PrPC via interaction with glycosaminoglycans. In conclusion, this is a mechanism by which the cellular production of the neurotoxic A is regulated by PrPC and may have implications for both Alzheimer's and prion diseases.
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Author contributions: E.T.P., J.C.M., and N.M.H. designed research; E.T.P., N.T.W., I.H., E.A.E., C.B.E., and H.N.B. performed research; E.T.P., N.T.W., E.A.E., C.B.E., and N.M.H. analyzed data; I.H., E.A.E., and C.B.E. contributed new reagents/analytic tools; and E.T.P., J.C.M., A.J.T., and N.M.H. wrote the paper.
The authors declare no conflict of interest.
Present address: Department of Biological Sciences, Lancaster University, Lancaster LA1 4YQ, United Kingdom.
**To whom correspondence should be addressed.
Nigel M. Hooper, E-mail:
n.m.hooper@leeds.ac.uk
www.pnas.org/cgi/doi/10.1073/pnas.0609621104
http://www.pnas.org/cgi/content/abst...9621104v1?etoc
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