FTO Is Involved in Alzheimer's Disease by Targeting TSC1-mTOR-Tau Signaling

Biochem Biophys Res Commun. 2018 Mar 25;498(1):234-239. doi: 10.1016/j.bbrc.2018.02.201. Epub 2018 Mar 2.

Abstract

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.

Keywords: AD; Diabetes; FTO; Insulin resistance; TSC1; Tau; mTOR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / pathology
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / deficiency
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / metabolism*
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology*
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / pathology
  • Male
  • Mice, Knockout
  • Obesity / metabolism
  • Obesity / pathology
  • Phosphorylation
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / metabolism*
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins / metabolism*
  • tau Proteins / metabolism*

Substances

  • TSC1 protein, human
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • tau Proteins
  • FTO protein, mouse
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • TOR Serine-Threonine Kinases