Mammalian target of rapamycin hyperactivity mediates the detrimental effects of a high sucrose diet on Alzheimer's disease pathology

Miranda E. Orr, Angelica Salinas, Rochelle Buffenstein, Salvatore Oddo

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1233-1242
Number of pages10
JournalNeurobiology of Aging
Volume35
Issue number6
DOIs
StatePublished - Jun 2014

Fingerprint

Sirolimus
Sucrose
Alzheimer Disease
Pathology
Diet
Insulin
Disease Susceptibility
Brain
Amyloid
Vascular Resistance
Insulin Resistance
Homeostasis
Animal Models
Obesity
Eating
Phosphorylation
Food

Keywords

  • Amyloid-β
  • APP
  • Diabetes
  • Insulin resistance
  • Tangles
  • Tau

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology
  • Medicine(all)

Cite this

Mammalian target of rapamycin hyperactivity mediates the detrimental effects of a high sucrose diet on Alzheimer's disease pathology. / Orr, Miranda E.; Salinas, Angelica; Buffenstein, Rochelle; Oddo, Salvatore.

In: Neurobiology of Aging, Vol. 35, No. 6, 06.2014, p. 1233-1242.

Research output: Contribution to journalArticle

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