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

NEUROBIOLOGY OF AGING

卷:35

Article

Orr, Miranda E.^1,2  Salinas, Angelica^1,2  Buffenstein, Rochelle^1,2  Oddo, Salvatore^1,2,3,4 

[1] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA

[2] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA

[3] Banner Sun Hlth Res Inst, Sun City, AZ USA

[4] Univ Arizona, Coll Med Phoenix, Dept Basic Med Sci, Phoenix, AZ USA

关键词: Amyloid-beta;    APP;    Tau;    Tangles;    Insulin resistance;    Diabetes;   

DOI  :  10.1016/j.neurobiolaging.2013.12.006

来源: Elsevier

【 摘 要 】

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-beta 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. (C) 2014 Elsevier Inc. All rights reserved.

【 授权许可】

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