FTO is involved in Alzheimer's disease by targeting TSC1-mTOR-Tau signaling.

Autor: Li H; Department of Neurology, The First People's Hospital of Chang Zhou, Jiang Su, China; The Third Affiliated Hospital of Soochow University, China. Electronic address: lihuajie0589@souhu.com., Ren Y; Department of Neurology, The First People's Hospital of Chang Zhou, Jiang Su, China; The Third Affiliated Hospital of Soochow University, China., Mao K; Department of Neurology, The First People's Hospital of Chang Zhou, Jiang Su, China; The Third Affiliated Hospital of Soochow University, China., Hua F; Department of Endocrinology, The First People's Hospital of Chang Zhou, Jiang Su, China; The Third Affiliated Hospital of Soochow University, China., Yang Y; Department of Neurosurgery, The First People's Hospital of ChangZhou Jiang Su, China; The Third Affiliated Hospital of Soochow University, China., Wei N; Department of Neurology, The First People's Hospital of Chang Zhou, Jiang Su, China; The Third Affiliated Hospital of Soochow University, China., Yue C; Department of Neurology, The First People's Hospital of Chang Zhou, Jiang Su, China; The Third Affiliated Hospital of Soochow University, China., Li D; Department of Neurology, The First People's Hospital of Chang Zhou, Jiang Su, China; The Third Affiliated Hospital of Soochow University, China., Zhang H; Department of Neurology, The First People's Hospital of Chang Zhou, Jiang Su, China; The Third Affiliated Hospital of Soochow University, China.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2018 Mar 25; Vol. 498 (1), pp. 234-239. Date of Electronic Publication: 2018 Mar 02.
DOI: 10.1016/j.bbrc.2018.02.201
Abstrakt: Diabetes and obesity are commonly associated with Alzheimer's disease (AD). Accumulating evidence show that insulin signaling defects are protentional upstream driver of AD. However, the mechanism by which diabetes and insulin signaling defects contribute to AD remains unknown. Here we show that Fat mass and obesity-associated protein (FTO) is involved the insulin defects-associated AD. Defective insulin signaling in diabetes and obesity in human and mice activated Fto in the brain tissues. Lentivirus-mediated knockdown of Fto reduced the phosphorylation of Tau protein whereas overexpression of FTO promoted the level of phosphorylated Tau in neurons. Mechanism study demonstrated that FTO activated the phosphorylation of Tau in a mTOR-dependent manner because FTO activated mTOR and its downstream signaling and rapamycin blocked FTO-mediated phosphorylation of Tau. FTO promoted the activation of mTOR by increasing the mRNA level of TSC1 but not TSC2, the upstream inhibitor of mTOR. Finally, we found that conditional knockout of Fto in the neurons reduced the cognitive deficits in 3xTg AD mice. Collectively, our evidence demonstrated that FTO is critically involved in insulin defects-related AD.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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