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Enhanced amyloid-beta generation by gamma-secretase complex in DRM microdomains with reduced cholesterol levels
| Title: | Enhanced amyloid-beta generation by gamma-secretase complex in DRM microdomains with reduced cholesterol levels |
| Authors: | Hata, Saori Browse this author →KAKEN DB | | Hu, Anqi Browse this author | | Piao, Yi Browse this author | | Nakaya, Tadashi Browse this author →KAKEN DB | | Taru, Hidenori Browse this author →KAKEN DB | | Morishima-Kawashima, Maho Browse this author →KAKEN DB | | Murayama, Shigeo Browse this author | | Nishimura, Masaki Browse this author | | Suzuki, Toshiharu Browse this author →KAKEN DB |
| Issue Date: | 1-Feb-2020 |
| Publisher: | Oxford University Press |
| Journal Title: | Human molecular genetics |
| Volume: | 29 |
| Issue: | 3 |
| Start Page: | 382 |
| End Page: | 393 |
| Publisher DOI: | 10.1093/hmg/ddz297 |
| Abstract: | A neuropathologic hallmark of Alzheimer's disease (AD) is the presence of senile plaques that contain neurotoxic amyloid-beta protein (A beta) species, which are generated by the cleavage of amyloid beta-protein precursor by secretases such as the gamma-secretase complex, preferentially located in detergent-resistant membrane (DRM) regions and comprising endoproteolysed amino- and carboxy-terminal fragments of presenilin, nicastrin, anterior pharynx defective 1 and presenilin enhancer 2. Whereas some of familial AD patients harbor causative PSEN mutations that lead to more generation of neurotoxic A beta 42, the contribution of A beta 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 beta 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 gamma-secretase components and A beta 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 beta generation. |
| Rights: | This is a pre-copyedited, author-produced version of an article accepted for publication in Human molecular genetics following peer review. The version of record Hata, Saori et al. Enhanced amyloid-beta generation by gamma-secretase complex in DRM microdomains with reduced cholesterol Levels. Human Molecular Genetics, Volume 29, Issue 3, 1 February 2020, Pages 382–393 is available online at: https://doi.org/10.1093/hmg/ddz297 |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/80318 |
| Appears in Collections: | 薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 鈴木 利治
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