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J. Biol. Chem., Vol. 282, Issue 50, 36275-36282, December 14, 2007

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Intake of Sucrose-sweetened Water Induces Insulin Resistance and Exacerbates Memory Deficits and Amyloidosis in a Transgenic Mouse Model of Alzheimer Disease^*

Dongfeng Cao, Hailin Lu, Terry L. Lewis, and Ling Li^¶||1

From the Departments of Medicine, ^¶Neurobiology, Pathology, and ^||Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294

Compelling evidence indicates that excess consumption of sugar-sweetened beverages plays an important role in the epidemic of obesity, a major risk factor for type 2 diabetes mellitus. Type 2 diabetes mellitus has been associated with a higher incidence of Alzheimer disease (AD). High fat diets promote AD-like pathology in mice. It is not known whether consumption of excess sugar as in calorically sweetened beverages with an otherwise normal diet affects the development of AD. In the present study, we provided 10% sucrose-sweetened water to a transgenic mouse model of AD with a normal rodent diet. Compared with the control mice with no sucrose added in the water, the sucrose group gained more body weight and developed glucose intolerance, hyperinsulinemia, and hypercholesterolemia. These metabolic changes were associated with the exacerbation of memory impairment and a 2–3-fold increase in insoluble amyloid-β protein levels and deposition in the brain. We further showed that the levels of expression and secretase-cleaved products of amyloid-β precursor protein were not affected by sucrose intake. The steady-state levels of insulin-degrading enzyme did not change significantly, whereas there was a 2.5-fold increase in brain apoE levels. Therefore, we concluded that the up-regulation of apoE accelerated the aggregation of Aβ, resulting in the exacerbation of cerebral amyloidosis in sucrose-treated mice. These data underscore the potential role of dietary sugar in the pathogenesis of AD and suggest that controlling the consumption of sugar-sweetened beverages may be an effective way to curtail the risk of developing AD.

Received for publication, April 30, 2007 , and in revised form, October 4, 2007.

^* This study was supported in part by Alzheimer's Association Grant IIRG-05-13139 and National Institutes of Health Grant AG025949. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 1808 7th Ave. S., BDB 658, Birmingham, AL 35294. Tel.: 205-934-1889; Fax: 205-975-8079; E-mail: lili{at}uab.edu.

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