Prediabetes-induced vascular alterations exacerbate central pathology in APPswe/PS1dE9 mice

Age remains the main risk factor for developing Alzheimer's disease (AD) although certain metabolic alterations, including prediabetes and hyperinsulinemia, also increase this risk. We present a mouse model of AD (APPswe/PS1dE9 mouse) with severe hyperinsulinemia induced by long-term high fat diet (HFD) treatment. After 23 weeks on HFD learning and memory processes were compromised. We observed a significant increase in tau hyperphosphorylation and A beta pathology, including A beta levels and amyloid burden. Microglia activation was also significantly increased in HFD-treated mice, both in close proximity to and far from senile plaques. Insulin degrading enzyme and neprilysin levels were not affected, suggesting that A beta degradation pathways were preserved, whereas we detected an increase in spontaneous cortical bleeding that could underlay an impairment of A beta interstitial fluid drainage, contributing to the increase in A beta deposition in APP/PS1-HFD mice. Altogether our data suggest that early hyperinsulinemia is enough to exacerbate AD pathology observed in APP/PS1 mice, and supports the role of insulin-resistance therapies to stop or delay central complications associated. (C) 2014 Elsevier Ltd. All rights reserved.