Role of insulin signaling in the interaction between Alzheimer disease and diabetes mellitus: a missing link to therapeutic potential.

Diabetes mellitus (DM) is one of the major non-genetic risk factors for Alzheimer disease (AD). However, the mechanism by which DM increases the risk of AD has not been elucidated. Here, we summarize recent findings to address this question. Whereas neuropathological studies in humans suggest that DM does not increase Aβ accumulation in the brain (a major hallmark of AD), earlier works in animal models show that Aβ does accumulate. Therefore, alternate mechanisms might exist. Recent studies using the human brain indicate that insulin signaling is impaired in the AD brain. In neurons, this insulin signaling plays a key role in modulating synaptic function and neuronal senescence besides regulating tau phosphorylation, another hallmark of AD. On the other hand, in cerebrovessels, DM causes vascular remodeling, which involves increased RAGE (receptor for advanced glycation endproducts) expression, and AD is associated with cerebrovascular amyloid angiopathy (CAA). Our recent study involving AD mice with DM has revealed that a vicious circle underlies the interaction between AD and DM. Interestingly, in our mouse model, AD increased RAGE expression, and DM worsened CAA. The contribution of vascular factors such as RAGE expression and CAA to the impairment of insulin signaling will be discussed. This impaired insulin signaling might be a possible link between AD and DM. Moreover, insulin signaling is also involved in the mechanism of aging, decreasing with an increase in age. An identification of the mechanism whereby DM modifies the pathological condition of AD through the modulation of insulin signaling is required to develop potential therapeutics for AD not only with but also without DM.