{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:46:03Z","timestamp":1791409563545,"version":"4.3.3"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"26","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,6,26]]},"abstract":"<jats:p>\n                    Proteolytic processing of the amyloid precursor protein (APP) by \u03b2-secretase, \u03b2-site APP cleaving enzyme (BACE1), is the initial step in the production of the amyloid \u03b2 (A\u03b2) peptide, which is involved in the pathogenesis of Alzheimer's disease. The normal cellular function of the prion protein (PrP\n                    <jats:sup>C<\/jats:sup>\n                    ), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt\u2013Jakob disease in humans, remains enigmatic. Because both APP and PrP\n                    <jats:sup>C<\/jats:sup>\n                    are subject to proteolytic processing by the same zinc metalloproteases, we tested the involvement of PrP\n                    <jats:sup>C<\/jats:sup>\n                    in the proteolytic processing of APP. Cellular overexpression of PrP\n                    <jats:sup>C<\/jats:sup>\n                    inhibited the \u03b2-secretase cleavage of APP and reduced A\u03b2 formation. Conversely, depletion of PrP\n                    <jats:sup>C<\/jats:sup>\n                    in mouse N2a cells by siRNA led to an increase in A\u03b2 peptides secreted into the medium. In the brains of PrP knockout mice and in the brains from two strains of scrapie-infected mice, A\u03b2 levels were significantly increased. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases failed to inhibit the \u03b2-secretase cleavage of APP. Using constructs of PrP, we show that this regulatory effect of PrP\n                    <jats:sup>C<\/jats:sup>\n                    on the \u03b2-secretase cleavage of APP required the localization of PrP\n                    <jats:sup>C<\/jats:sup>\n                    to cholesterol-rich lipid rafts and was mediated by the N-terminal polybasic region of PrP\n                    <jats:sup>C<\/jats:sup>\n                    via interaction with glycosaminoglycans. In conclusion, this is a mechanism by which the cellular production of the neurotoxic A\u03b2 is regulated by PrP\n                    <jats:sup>C<\/jats:sup>\n                    and may have implications for both Alzheimer's and prion diseases.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0609621104","type":"journal-article","created":{"date-parts":[[2007,6,16]],"date-time":"2007-06-16T07:57:26Z","timestamp":1181980646000},"page":"11062-11067","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":236,"title":["Cellular prion protein regulates \u03b2-secretase cleavage of the Alzheimer's amyloid precursor protein"],"prefix":"10.1073","volume":"104","author":[{"given":"Edward T.","family":"Parkin","sequence":"first","affiliation":[{"name":"*Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, and"},{"name":"Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole T.","family":"Watt","sequence":"additional","affiliation":[{"name":"*Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, and"},{"name":"Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ishrut","family":"Hussain","sequence":"additional","affiliation":[{"name":"Neurodegeneration Research, Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Limited, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Eckman","sequence":"additional","affiliation":[{"name":"Mayo Clinic, Jacksonville, FL 32224; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher B.","family":"Eckman","sequence":"additional","affiliation":[{"name":"Mayo Clinic, Jacksonville, FL 32224; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean C.","family":"Manson","sequence":"additional","affiliation":[{"name":"Roslin Institute, Neuropathogenesis Unit, Edinburgh EH9 3JF, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert N.","family":"Baybutt","sequence":"additional","affiliation":[{"name":"Roslin Institute, Neuropathogenesis Unit, Edinburgh EH9 3JF, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Turner","sequence":"additional","affiliation":[{"name":"*Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel 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