Inflammation, insulin signaling and cognitive function in aged APP/PS1 mice

Cognitive dysfunction and neuroinflammation are typical in Alzheimer's disease (AD), but are also associated with normal aging, albeit less severely. Insulin resistance in the brain has been demonstrated in AD patients and is thought to be involved in AD pathophysiology. Using 15-18 month-old APP/PSI mice, this study measured peripheral and central insulin signaling and sensitivity, inflammatory markers in brain and plasma and oxidative stress and synapse density in the brain. Novel object recognition, Morris water maze and reversal water maze tasks were performed to assess cognitive function in aged APP/PSI mice and wild type littermates. Glucose tolerance and insulin sensitivity were similar in APP/PSI mice and wild type controls, however IRS-1 pSer(616) was increased in cortex and dentate gyrus of APP/PSI mice. Recognition and spatial memory was impaired in both APP/PSI and wild type mice, however learning impairments were apparent in APP/PSI mice. Expression of GLP-1 receptor, ERK2, IKK beta, mTOR, PKC theta, NF-kappa beta 1 and TLR4 was similar between aged APP/PSI mice and age-matched wild types. Compared to age-matched wild type mice, IFN gamma and IL-4 were increased in brains of APP/PSI mice. These results suggest that normal aging may be associated with enhanced neuroinflammation, oxidative stress, and cognitive decline, however distinctions are apparent in the brain of APP/PSI mice in terms of inflammation and insulin signaling and in certain cognitive domains. Demarcation of pathological events that distinguish AD from normal aging will allow for improvements in diagnostic tools and the development of more effective therapeutics. (C) 2018 Elsevier Inc. All rights reserved.