Published on March 25, 2018 in Biochem Biophys Res Commun volume 498(1).

PubMed ID: 29501742

DOI: S0006-291X(18)30457-1

Abstract:

Diabetes and obesity are commonly associated with Alzheimer's disease (AD).Accumulating evidence show that insulin signaling defects are protentional upstreamdriver of AD. However, the mechanism by which diabetes and insulin signaling defectscontribute to AD remains unknown. Here we show that Fat mass and obesity-associatedprotein (FTO) is involved the insulin defects-associated AD. Defective insulinsignaling in diabetes and obesity in human and mice activated Fto in the braintissues. Lentivirus-mediated knockdown of Fto reduced the phosphorylation of Tauprotein whereas overexpression of FTO promoted the level of phosphorylated Tau inneurons. Mechanism study demonstrated that FTO activated the phosphorylation of Tauin a mTOR-dependent manner because FTO activated mTOR and its downstream signalingand rapamycin blocked FTO-mediated phosphorylation of Tau. FTO promoted theactivation of mTOR by increasing the mRNA level of TSC1 but not TSC2, the upstreaminhibitor of mTOR. Finally, we found that conditional knockout of Fto in the neuronsreduced the cognitive deficits in 3xTg AD mice. Collectively, our evidencedemonstrated that FTO is critically involved in insulin defects-related AD.CI - Copyright © 2018 Elsevier Inc. All rights reserved.