P3–067: Neuronal leptin resistance in Alzheimer's disease

Recently, leptin signaling has received considerable attention in the Alzheimer disease (AD) field with its pathophysiological implication and therapeutic potential. Previously, leptin has been demonstrated to attenuate tau hyperphosphorylation in neuronal cells and has been shown to be modulated by amyloid-β Moreover, its role in neuroprotection and neurogenesis within the hippocampus has been shown in animal models. Therefore, the signaling pathway induced by leptin may play an important role in the pathogenesis of AD while its mechanism is unclear. To understand the mechanism, in this study, we investigated the status of leptin signaling pathway in AD brains. To further characterize the association between leptin signaling and vulnerable neurons in AD, we assessed the profile of leptin and the leptin receptor in AD and control patients. We analyzed the concentration of leptin in cerebrospinal fluid (CSF) as well as the concentration and localization of leptin, and the full-length leptin receptor, in the hippocampi of AD and control patients. Significant elevations in the level of leptin in both CSF and hippocampal tissue of AD patients, when compared to age-matched control cases, indicate a physiological upregulation of leptin in the disease. However, leptin receptor mRNA levels were decreased in AD brain tissue, and the leptin receptor protein was strikingly co-aggregated with neurofibrillary tangles, suggesting a severe discontinuity in the leptin signaling pathway in AD. Our results strongly suggest that leptin resistance in the hippocampus may play a role in the characteristic changes associated with the disease. These findings are the first to demonstrate such dysregulated leptin-signaling circuitry and provide novel insights into the possible role of aberrant leptin signaling in AD. The pathological implication of neuronal leptin resistance and its molecular mechanism will be discussed further in the presentation.