AbstractThe development of intraneuronal lesions as a result of the progressive deposition of hyperphosphorylated tau at specific brain regions (such as hippocampus and cortex) plays a key role in the pathological process of Alzheimer's disease. However, the mechanisms by which tau phosphorylation is regulated, mainly in the pathology found in the cortex, are still poorly understood. Here, we analyzed the effect of cortistatin, a cortical neuropeptide related to somatostatin, on tau phosphorylation at Ser262 in cultures of murine cortical neurons. Both somatostatin and cortistatin induce tau phosphorylation at Ser262, a site modified in Alzheimer's disease, although with different kinetics in cortex. The effect of cortistatin likely is mediated by heterodimeric receptors composed of somatostatin receptor subtypes 2 and 4 and also by protein kinase C signaling. Cortistatin‐deficient mice show decreased tau phosphorylation at Ser262 in the cortex but not in other brain regions tested. Our results suggest an important role for cortistatin in the regulation of tau phosphorylation that may be associated with the pathophysiology of Alzheimer's disease in regions such as the cerebral cortex. © 2008 Wiley‐Liss, Inc.