P1-106: ABERRANT ACTIVATION OF PKC-THETA IN ALZHEIMER'S DISEASE AND ITS ROLE IN NEURONAL INSULIN RESISTANCE

Severe abnormalities in brain insulin signaling have been documented to play a pivotal role in the pathogenesis of Alzheimer's disease (AD). Indeed, the “insulin-resistant brain state” has been hypothesized to form the core of the neurodegenerative events that occur in AD. In fact, insulin administration improved cognitive performance in AD patients, reinforcing the idea that abnormalities in brain insulin function and insulin signal pathway are the major factors that mechanistically influence the onset and development of AD. However, the underlying mechanism leading to impaired insulin signaling pathway in neurons remains to be elucidated. PKC theta, a key modulator of insulin signaling in peripheral tissues, is shown to be related with insulin resistance in hypothalamic neurons by modulating insulin signaling. Given that PKC theta is expressed in neurons including those of the hippocampus and cerebral cortex which are particularly vulnerable brain regions of AD, we sought to determine the pathological role of PKC theta in AD. The expression pattern of PKC theta in AD was analyzed by immunohistochemistry and immunoblot analysis. The mechanistic role of PKC theta in insulin pathway was examined in neuronal cell culture and animal models with various molecular and biochemical assays. With multiple experimental approaches, we found that the level of PKC theta was increased in the vulnerable neurons in AD with alterations in other insulin signaling proteins. We also found that the regulation of PKC theta modulates the insulin-mediated signaling pathway and induces tau pathology in neuronal cells. Collectively, our data strongly suggest the pathophysiological importance of PKC theta in the regulation of insulin signaling in neurons and dysregulation of PKC theta may be an underlying mechanism of neuronal insulin resistance in AD.