title: Endoplasmic reticulum stress enhances γ-secretase activity.
abstract: The endoplasmic reticulum (ER) copes with unfolded proteins in the lumen (ER stress) by activating three distinct intracellular signaling pathways of unfolded protein response (UPR). ER stress contributes to the pathogenesis of obesity and diabetes, which are risk factors for Alzheimer's disease (AD) that accelerate the pathogenesis of AD. However, whether ER stress is involved in the development of AD remains unclear. In this study, we demonstrate that ER stress induces presenilin-1 expression through activating transcription factor 4 (ATF4), resulting in increased amyloid-β (Aβ) secretion by γ-secretase activity, which is suppressed by quercetin by modifying UPR signaling. This result suggests that ER stress may be stimulated in obesity and type 2 diabetes, thereby enhancing γ-secretase activity that is the underlying molecular mechanism affecting the pathogenesis of AD.
authors: Department of Neurobiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Kazunori
authors: K
authors: Ohta
authors: Akihito
authors: A
authors: Mizuno
authors: Shimo
authors: S
authors: Li
authors: Masanori
authors: M
authors: Itoh
authors: Masashi
authors: M
authors: Ueda
authors: Eri
authors: E
authors: Ohta
authors: Yoko
authors: Y
authors: Hida
authors: Miao-xing
authors: MX
authors: Wang
authors: Manabu
authors: M
authors: Furoi
authors: Yukihiro
authors: Y
authors: Tsuzuki
authors: Mitsuaki
authors: M
authors: Sobajima
authors: Yoshimasa
authors: Y
authors: Bohmoto
authors: Tatsuya
authors: T
authors: Fukushima
authors: Masuko
authors: M
authors: Kobori
authors: Takashi
authors: T
authors: Inuzuka
authors: Toshiyuki
authors: T
authors: Nakagawa
mesh_terms: D051701:Activating Transcription Factor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011794:Quercetin / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000378:metabolism
chemical_list: D051881:Receptor, Notch1; D051701:Activating Transcription Factor 4; D011794:Quercetin; D053829:Amyloid Precursor Protein Secretases