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However, identification of \u03b3-secretase inhibitors has also uncovered mechanism-based side effects. One approach to circumvent these side effects has been modulation of \u03b3-secretase to shift A\u03b2 production to favor shorter, less amyloidogenic peptides than A\u03b2<jats:sub>42<\/jats:sub>, without affecting the overall cleavage efficiency of the enzyme. This approach, frequently called \u03b3-secretase modulation, appears more promising and has lead to the development of new therapeutic candidates for disease modification in Alzheimer\u2019s disease.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Here we describe EVP-0015962, a novel small molecule \u03b3-secretase modulator. EVP-0015962 decreased A\u03b2<jats:sub>42<\/jats:sub> in H4 cells (IC<jats:sub>50<\/jats:sub> = 67 nM) and increased the shorter A\u03b2<jats:sub>38<\/jats:sub> by 1.7 fold at the IC<jats:sub>50<\/jats:sub> for lowering of A\u03b2<jats:sub>42<\/jats:sub>. A\u03b2<jats:sub>Total<\/jats:sub>, as well as other carboxyl-terminal fragments of amyloid precursor protein, were not changed. EVP-0015962 did not cause the accumulation of other \u03b3-secretase substrates, such as the Notch and ephrin A4 receptors, whereas a \u03b3-secretase inhibitor reduced processing of both. A single oral dose of EVP-0015962 (30 mg\/kg) decreased A\u03b2<jats:sub>42<\/jats:sub> and did not alter A\u03b2<jats:sub>Total<\/jats:sub> peptide levels in a dose-dependent manner in Tg2576 mouse brain at an age when overt A\u03b2 deposition was not present. In Tg2576 mice, chronic treatment with EVP-0015962 (20 or 60 mg\/kg\/day in a food formulation) reduced A\u03b2 aggregates, amyloid plaques, inflammatory markers, and cognitive deficits.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>EVP-0015962 is orally bioavailable, detected in brain, and a potent, selective \u03b3-secretase modulator <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. Chronic treatment with EVP-0015962 was well tolerated in mice and lowered the production of A\u03b2<jats:sub>42<\/jats:sub>, attenuated memory deficits, and reduced A\u03b2 plaque formation and inflammation in Tg2576 transgenic animals. In summary, these data suggest that \u03b3-secretase modulation with EVP-0015962 represents a viable therapeutic alternative for disease modification in Alzheimer\u2019s disease.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1750-1326-7-61","type":"journal-article","created":{"date-parts":[[2012,12,18]],"date-time":"2012-12-18T15:59:53Z","timestamp":1355846393000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":76,"title":["Modulation of \u03b3-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice"],"prefix":"10.1186","volume":"7","author":[{"given":"Kathryn","family":"Rogers","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin M","family":"Felsenstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori","family":"Hrdlicka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiming","family":"Tu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faris","family":"Albayya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winnie","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Hopp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary-Jo","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darcie","family":"Spaulding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilliary","family":"Hodgdon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Nolan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melody","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Francois","family":"Blain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Freeman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"De Strooper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veerle","family":"Vulsteke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Scrocchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Portelius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Hutter-Paier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Havas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ahlijanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothy","family":"Flood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liza","family":"Leventhal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gideon","family":"Shapiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Patzke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Chesworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Koenig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2012,12,18]]},"reference":[{"key":"381_CR1","first-page":"146","volume":"64","author":"A Alzheimer","year":"1907","unstructured":"Alzheimer A: \u00dcber eine eigenartige erkrankung der hirnrinde. 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