LAUSR

Over 380 million people worldwide suffer from type II diabetes mellitus (T2DM),andanestimated43millioncurrentlysuffer from Alzheimer’s disease (AD). These numbers are expected to grow rapidly with the increasing population longevity. Moreover, T2DM is a significant risk factor for the development of AD. Given the significant global health impact and epidemiological associations, much effort was devoted to understanding the molecular mechanisms linking these two diseases. Chronic inflammation, direct insulin effects in the brain, and vascular dysfunction, among many others, have been suggested to explain this association. Further, similarities in gene expression between pancreatic islet cells and neurons were also described. Recently, Karki et al. used in silico pathwaymodeling to propose that the activation of shared signaling pathways can not only explain this comorbidity, but also the effects of T2DM medications in altering the risk of AD. In this issue of BioEssays, Tsutsui and Hays propose another mechanism that can explain the association between T2DM and AD. The authors propose the hypothesis that increased intracellular Ca2þ accumulation in diseased cells leads to altered signaling by changing the localization and proteinprotein interactions of key signaling mediators and scaffolding proteins. Tsutsui and Hays discuss how Ca2þ can determine the overall affinity of phosphotyrosine binding domains with membrane phospholipids and interacting protein partners. By altering the partitioning of these proteins between the cytosol and membrane surface, and by favoring a subset of protein– protein interactions over others, Ca2þ can profoundly change the outcomes and signaling intensity of receptor activation. The authors use the p52Shc/Src axis as an example, in which high intracellular Ca2þ modifies the outcome of insulin and NMDA receptors, from activation of PI3K/Akt and MAPK pathways in normal cells, to a pathogenic JNK pathway in T2DM and AD. JNK activation would then lead to reduced PI3K signaling, insulin resistance, and neuronal loss. This mechanism has the