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Whereas some of familial AD patients harbor causative PSEN mutations that lead to more generation of neurotoxic A\u03b242, the contribution of A\u03b2 generation to sporadic\/late-onset AD remains unclear. We found that the carboxy-terminal fragment of presenilin 1 was redistributed from DRM regions to detergent-soluble membrane (non-DRM) regions in brain tissue samples from individuals with sporadic AD. DRM fractions from AD brain sample had the ability to generate significantly more A\u03b2 and had a lower cholesterol content than DRM fractions from non-demented control subjects. We further demonstrated that lowering the cholesterol content of DRM regions from cultured cells contributed to the redistribution of \u03b3-secretase components and A\u03b2 production. Taken together, the present analyses suggest that the lowered cholesterol content in DRM regions may be a cause of sporadic\/late-onset AD by enhancing overall A\u03b2 generation.<\/jats:p>","DOI":"10.1093\/hmg\/ddz297","type":"journal-article","created":{"date-parts":[[2019,12,6]],"date-time":"2019-12-06T12:44:23Z","timestamp":1575636263000},"page":"382-393","source":"Crossref","is-referenced-by-count":6,"title":["Enhanced amyloid-\u03b2 generation by \u03b3-secretase complex in DRM microdomains with reduced cholesterol levels"],"prefix":"10.1093","volume":"29","author":[{"given":"Saori","family":"Hata","sequence":"first","affiliation":[{"name":"Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anqi","family":"Hu","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Piao","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Nakaya","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidenori","family":"Taru","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maho","family":"Morishima-Kawashima","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan"},{"name":"Department of Molecular Neuropathology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeo","family":"Murayama","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Molecular Neuroscience Research Center, Shiga University of Medical Science, Shiga 520-2192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiharu","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,12,16]]},"reference":[{"key":"2020021222031263600_ref1","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.jalz.2013.02.003","article-title":"2013 Alzheimer\u2019s disease facts and figures","volume":"9","author":"Thies","year":"2013","journal-title":"Alzheimers Dement."},{"key":"2020021222031263600_ref2","doi-asserted-by":"crossref","first-page":"965","DOI":"10.3233\/JAD-171145","article-title":"Alzheimer\u2019s disease: a journey from amyloid peptides and oxidative stress, to biomarker technologies and disease prevention strategies-gains from AIBL and DIAN cohort studies","volume":"62","author":"Martins","year":"2018","journal-title":"J. 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