{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:07:38Z","timestamp":1791230858990,"version":"4.1.0"},"reference-count":36,"publisher":"Wiley","license":[{"start":{"date-parts":[[2012,1,1]],"date-time":"2012-01-01T00:00:00Z","timestamp":1325376000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["International Journal of Alzheimer's Disease"],"published-print":{"date-parts":[[2012]]},"abstract":"<jats:p>The Amyloid Hypothesis states that the cascade of events associated with Alzheimer's disease (AD)\u2014formation of amyloid plaques, neurofibrillary tangles, synaptic loss, neurodegeneration, and cognitive decline\u2014are triggered by A<jats:italic>\u03b2<\/jats:italic>peptide dysregulation (Kakuda et al., 2006, Sato et al., 2003, Qi-Takahara et al., 2005). Since<jats:italic>\u03b3<\/jats:italic>-secretase is critical for A<jats:italic>\u03b2<\/jats:italic>production, many in the biopharmaceutical community focused on<jats:italic>\u03b3<\/jats:italic>-secretase as a target for therapeutic approaches for Alzheimer's disease. However, pharmacological approaches to control<jats:italic>\u03b3<\/jats:italic>-secretase activity are challenging because the enzyme has multiple, physiologically critical protein substrates. To lower amyloidogenic A<jats:italic>\u03b2<\/jats:italic>peptides without affecting other<jats:italic>\u03b3<\/jats:italic>-secretase substrates, the epsilon (<jats:italic>\u03b5<\/jats:italic>) cleavage that is essential for the activity of many substrates must be preserved. Small molecule modulators of<jats:italic>\u03b3<\/jats:italic>-secretase activity have been discovered that spare the<jats:italic>\u03b5<\/jats:italic>cleavage of APP and other substrates while decreasing the production of A<jats:italic>\u03b2<\/jats:italic><jats:sub>42<\/jats:sub>. Multiple chemical classes of<jats:italic>\u03b3<\/jats:italic>-secretase modulators have been identified which differ in the pattern of A<jats:italic>\u03b2<\/jats:italic>peptides produced. Ideally, modulators will allow the<jats:italic>\u03b5<\/jats:italic>cleavage of all substrates while shifting APP cleavage from A<jats:italic>\u03b2<\/jats:italic><jats:sub>42<\/jats:sub>and other highly amyloidogenic A<jats:italic>\u03b2<\/jats:italic>peptides to shorter and less neurotoxic forms of the peptides without altering the total A<jats:italic>\u03b2<\/jats:italic>pool. Here, we compare chemically distinct modulators for effects on APP processing and<jats:italic>in vivo<\/jats:italic>activity.<\/jats:p>","DOI":"10.1155\/2012\/210756","type":"journal-article","created":{"date-parts":[[2012,12,19]],"date-time":"2012-12-19T08:37:18Z","timestamp":1355906238000},"page":"1-10","source":"Crossref","is-referenced-by-count":11,"title":["Modulation of Gamma-Secretase for the Treatment of Alzheimer's Disease"],"prefix":"10.1155","volume":"2012","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7488-8773","authenticated-orcid":true,"given":"Barbara","family":"Tate","sequence":"first","affiliation":[{"name":"Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy D.","family":"McKee","sequence":"additional","affiliation":[{"name":"Satori Pharmaceuticals, Inc., 281 Albany Street, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn M. 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