title: Mammalian target of rapamycin hyperactivity mediates the detrimental effects of a high sucrose diet on Alzheimer's disease pathology.
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.
authors.affiliation: Department of Physiology and The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Miranda E
authors.initials: ME
authors.lastname: Orr
authors.affiliation: Department of Physiology and The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Angelica
authors.initials: A
authors.lastname: Salinas
authors.affiliation: Department of Physiology and The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Rochelle
authors.initials: R
authors.lastname: Buffenstein
authors.affiliation: Department of Physiology and The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Banner Sun Health Research Institute, Sun City, AZ, USA; Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA. Electronic address: oddo@email.arizona.edu.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oddo
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D003920:Diabetes Mellitus / Q000209:etiology / Q000235:genetics; D019422:Dietary Sucrose / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D019422:Dietary Sucrose; D007328:Insulin; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: APP; Amyloid-β; Diabetes; Insulin resistance; Tangles; Tau