The roles of insulin signaling between diabetes and Alzheimer's disease

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Epidemiological studies suggest that diabetes mellitus increases the risk of onset of Alzheimer disease (AD). However, the underlying mechanisms have not been fully understood. Six months on a high fat diet increased Abeta40 in B6C mice brain. To investigate the effects of diabetes on AD, we further analyzed the phenotypes of APP+ob/ob mice, which showed the increased cerebral amyloid angiopathy and impaired insulin signaling, especially focusing on tau phosphorylation. 18 month old APP+ob/ob mice showed highly increased level of tau phosphorylation in the brain. Tau phosphorylation is increased by diabetes in APP mice, suggesting that Abeta is prerequisite, but insufficient to cause tau phosphorylation in vivo. Abeta accumulation, insulin signaling and tau phosphorylation might play essential roles in the pathological interaction between AD and diabetes.These results suggest that diabetes disrupts homeostasis against AD.