Mammalian Target of Rapamycin Hyperactivity Mediates the Detrimental Effects of a High Sucrose Diet on Alzheimer's Disease Pathology

Neurobiol Aging. 2014 Jun;35(6):1233-42. doi: 10.1016/j.neurobiolaging.2013.12.006. Epub 2013 Dec 14.

Abstract

High sugar consumption and diabetes increase the risk of developing Alzheimer's disease (AD) by unknown mechanisms. Using an animal model of AD, here we show that high sucrose intake induces obesity with changes in central and peripheral insulin signaling. These pre-diabetic changes are associated with an increase in amyloid-β production and deposition. Moreover, high sucrose ingestion exacerbates tau phosphorylation by increasing Cdk5 activity. Mechanistically, the sucrose-mediated increase in AD-like pathology results from hyperactive mammalian target of rapamycin (mTOR), a key nutrient sensor important in regulating energy homeostasis. Specifically, we show that rapamycin, an mTOR inhibitor, prevents the detrimental effects of sucrose in the brain without altering changes in peripheral insulin resistance. Overall, our data suggest that high sucrose intake and dysregulated insulin signaling, which are known to contribute to the occurrence of diabetes, increase the risk of developing AD by upregulating brain mTOR signaling. Therefore, early interventions to modulate mTOR activity in individuals at high risk of developing diabetes may decrease their AD susceptibility.

Keywords: APP; Amyloid-β; Diabetes; Insulin resistance; Tangles; Tau.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / etiology*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / prevention & control
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain
  • Cyclin-Dependent Kinase 5 / metabolism
  • Diabetes Mellitus / etiology
  • Diabetes Mellitus / genetics
  • Dietary Sucrose / adverse effects*
  • Disease Models, Animal
  • Female
  • Insulin / physiology
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology
  • Mice
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Phosphorylation / drug effects
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / physiology*
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • Dietary Sucrose
  • Insulin
  • tau Proteins
  • TOR Serine-Threonine Kinases
  • Cyclin-Dependent Kinase 5
  • Sirolimus