Enhanced amyloid-beta generation by gamma-secretase complex in DRM microdomains with reduced cholesterol levels

Hata, Saori; Hu, Anqi; Piao, Yi; Nakaya, Tadashi; Taru, Hidenori; Morishima-Kawashima, Maho; Murayama, Shigeo; Nishimura, Masaki; Suzuki, Toshiharu

Enhanced amyloid-beta generation by gamma-secretase complex in DRM microdomains with reduced cholesterol levels

Hata, Saori; Hu, Anqi; Piao, Yi et al.

Human molecular genetics, 2020, 29(3), 382-393

Permalink : https://hdl.handle.net/2115/80318

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アクセス権	open access
URI	https://hdl.handle.net/2115/80318
タイトル	Enhanced amyloid-beta generation by gamma-secretase complex in DRM microdomains with reduced cholesterol levels
著者	Hata, Saori ; Hu, Anqi ; Piao, Yi ; Nakaya, Tadashi ; Taru, Hidenori ; Morishima-Kawashima, Maho ; Murayama, Shigeo ; Nishimura, Masaki ; Suzuki, Toshiharu
e-Rad_Researcher 40581012 著者名 Hata, Saori
著者名 Hu, Anqi
著者名 Piao, Yi
e-Rad_Researcher 50374559 著者名 Nakaya, Tadashi
e-Rad_Researcher 30533731 著者名 Taru, Hidenori
e-Rad_Researcher 50204722 著者名 Morishima-Kawashima, Maho
著者名 Murayama, Shigeo
著者名 Nishimura, Masaki
e-Rad_Researcher 80179233 著者名 Suzuki, Toshiharu
言語	英語
発行日	2020-02-01
出版者	Oxford University Press
収録物名	Human molecular genetics
巻(号)	29(3)
ページ	382-393
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
権利情報	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
PISSN	0964-6906
関連情報 (isVersionOf)	出版社版DOI https://doi.org/10.1093/hmg/ddz297