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bioRxiv · 10.1101/863670

Acute inflammatory events attenuate high-sucrose diet-induced neurodegenerative processes in reproductively normal female wild-type mice

Pacholko, A. G.·Bekar, L. K.
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Abstract

It is known that diabetic and chronic inflammatory conditions can increase the risk of Alzheimers disease (AD)-like neurodegeneration in isolation. As certain elements of the diabetic/pre-diabetic state may sensitize the brain to inflammatory insult (i.e. excess glucocorticoid activity), there is reason to believe that obesogenic and inflammatory factors may accelerate neurodegeneration in a synergistic manner. Also, given that most AD research utilizes male animal models despite increased prevalence of AD among women, we sought to characterize elements of the established (in males) high-sucrose model of neurodegeneration, for the first time, in reproductively normal (pre-menopausal) female mice. A high-sucrose diet (20% of the drinking water) was combined with systemic intraperitoneal lipopolysaccharide (LPS) injections (0.1 mg/kg; 1x/month over 3 months) over seven months in reproductively normal female wild-type mice (C57Bl/6; n=10/group). Although a deleterious effect was hypothesized, low-dose LPS proved to protect against high sucrose diet-induced pathologies in female wild-type mice. Results from our high-sucrose group confirmed that a high-sucrose diet is a mild model of neurodegeneration in wild-type females, as evidenced by exaggerated glucocorticoid expression, spatial learning deficits, irregularities within the insulin pathway, and increased {beta}-amyloid production and Tau phosphorylation. While LPS had little to no effect in isolation, it exerted a protective influence when added to animals sustained on a high-sucrose diet. Corticosterone homeostasis, and levels of amyloid-{beta} (A{beta}) and pTau were rescued following addition of LPS. The work presented supports a high-sucrose diet as a model of mild neurodegeneration in female mice and highlights a protective role for transient inflammation against dietary-insult that may be sex dependent.

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Pacholko, A. G., Bekar, L. K.. 2019-12-03. Acute inflammatory events attenuate high-sucrose diet-induced neurodegenerative processes in reproductively normal female wild-type mice. https://doi.org/10.1101/863670

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