Budget Amount *help |
¥3,980,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥480,000)
Fiscal Year 2007: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2006: ¥1,900,000 (Direct Cost: ¥1,900,000)
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Research Abstract |
Development of effective Alzheimer's disease (AD) therapy is urgently required because AD currently affects nearly 2.5% of the population in industrialized countries. We have identified a novel neuroprotective peptide named humanin (HN) from an occipital lobe of an AD patient. Very recently, we also identified a novel cell-surface receptor for UN (HNR), which belongs to the IL-6 receptor family and is consisting of three subunits, WSX-1, CNTFRalpha, and gp 130. Analysis of the physiological function of HNR may lead to the development of an effective therapy for AD because the biological effect evoked by HN/HNR is likely to regulate the pathogenesis of AD. In this study, we performed i) analysis of the function of HNR, ii) development of a novel AD model with severe brain atrophy, iii) identification of HN/UN-like molecules, and iv) analysis of pharmacological effect of HN derivatives on AI) model mice. We found that the JAK2/STAT3 signaling axis mediates the anti-AD effect of HN/HNR. We also identified an 4 kDa HN-like molecule in testes and colons which can be transcriptionally regulated by lutenizing hormone (LH) or human chorionic gonadotropin (hCG). Moreover we found that intranasally administered Colivlein (CLN), the most potent HN derivative, completely suppressed memory impairment in a most common AD model termed Tg2576 (an APPswe transgenic mouse). In addition, we generated a novel AD model by crossing Tg2576 with HNR knockout mice and found that the mice developed memory impairment earlier than authentic Tg2576, supporting our hypothesis that HN/HNR function may play an important role in the pathogenesis of AD. This study provides a novel insight into therapy for AD.
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