{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:05:54Z","timestamp":1791266754023,"version":"4.1.0"},"reference-count":0,"publisher":"Walter de Gruyter GmbH","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biological Chemistry"],"published-print":{"date-parts":[[2012,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>\u03b3-Secretase is a membrane-embedded protease complex with presenilin as the catalytic component. Cleavage within the transmembrane domain of the amyloid \u03b2-protein precursor (APP) by \u03b3-secretase produces the C-terminus of the amyloid \u03b2-peptide (A\u03b2), a proteolytic product prone to aggregation and strongly linked to Alzheimer\u2019s disease (AD). Presenilin mutations are associated with early-onset AD, but their pathogenic mechanisms are unclear. One hypothesis is that these mutations cause AD through a toxic gain of function, changing \u03b3-secretase activity to increase the proportion of 42-residue A\u03b2 over the more soluble 40-residue form. A competing hypothesis is that the mutations cause AD through a loss of function, by reducing \u03b3-secretase activity. However, \u03b3-secretase apparently has two types of activities, an endoproteolytic function that first cuts APP to generate a 48\/49-residue form of A\u03b2, and a carboxypeptidase activity that processively trims these longer A\u03b2 intermediates approximately every three residues to form shorter, secreted forms. Recent studies suggest a resolution of the gain-of-function vs. loss-of-function debate: presenilin mutations may increase the proportion of longer, more aggregation-prone A\u03b2 by specifically decreasing the trimming activity of \u03b3-secretase. That is, the reduction of this particular proteolytic function of presenilin, not its endoproteolytic activity, may lead to the neurotoxic gain of function.<\/jats:p>","DOI":"10.1515\/hsz-2012-0140","type":"journal-article","created":{"date-parts":[[2012,8,21]],"date-time":"2012-08-21T15:27:56Z","timestamp":1345562876000},"page":"899-905","source":"Crossref","is-referenced-by-count":59,"title":["Processive proteolysis by \u03b3-secretase and the mechanism of Alzheimer\u2019s disease"],"prefix":"10.1515","volume":"393","author":[{"given":"Michael S.","family":"Wolfe","sequence":"first","affiliation":[{"name":"Center for Neurologic Diseases, Brigham and Women\u2019s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, H.I.M. 754, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2012,9,1]]},"container-title":["bchm"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.degruyter.com\/view\/j\/bchm.2012.393.issue-9\/hsz-2012-0140\/hsz-2012-0140.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyter.com\/document\/doi\/10.1515\/hsz-2012-0140\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyter.com\/document\/doi\/10.1515\/hsz-2012-0140\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T15:26:31Z","timestamp":1647271591000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.degruyter.com\/document\/doi\/10.1515\/hsz-2012-0140\/html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,9,1]]},"references-count":0,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2012,9,1]]},"published-print":{"date-parts":[[2012,9,1]]}},"alternative-id":["10.1515\/hsz-2012-0140"],"URL":"https:\/\/doi.org\/10.1515\/hsz-2012-0140","relation":{},"ISSN":["1437-4315","1431-6730"],"issn-type":[{"value":"1437-4315","type":"electronic"},{"value":"1431-6730","type":"print"}],"subject":[],"published":{"date-parts":[[2012,9,1]]}}}