Tsukamoto Emi, Hashimoto Yuichi, Kanekura Kohsuke, Niikura Takako, Aiso Sadakazu, Nishimoto Ikuo
Departments of Pharmacology and Anatomy, KEIO University School of Medicine, Shinjuku-ku, Tokyo, Japan.
J Neurosci Res. 2003 Sep 1;73(5):627-36. doi: 10.1002/jnr.10703.
Neuronal pathology of the brain with Alzheimer's disease (AD) is characterized by numerous depositions of amyloid-beta peptides (Abeta). Abeta binding to the 75-kDa neurotrophin receptor (p75NTR) causes neuronal cell death. Here we report that Abeta causes cell death in neuronal hybrid cells transfected with p75NTR, but not in nontransfected cells, and that p75NTR(L401K) cannot mediate Abeta neurotoxicity. We analyzed the cytotoxic pathway by transfecting pertussis toxin (PTX)-resistant G protein alpha subunits in the presence of PTX and identified that Galpha(o), but not Galpha(i), proteins are involved in p75NTR-mediated Abeta neurotoxicity. Further investigation suggested that Abeta neurotoxicity via p75NTR involved JNK, NADPH oxidase, and caspases-9/3 and was inhibited by activity-dependent neurotrophic factor, insulin-like growth factor-I, basic fibroblast growth factor, and Humanin, as observed in primary neuron cultures. Understanding the Abeta neurotoxic mechanism would contribute significantly to the development of anti-AD therapies.
阿尔茨海默病（AD）患者大脑的神经元病理学特征是β-淀粉样肽（Aβ）大量沉积。Aβ与75 kDa神经营养因子受体（p75NTR）结合会导致神经元细胞死亡。在此我们报告，Aβ可导致转染了p75NTR的神经元杂交细胞死亡，但不会导致未转染细胞死亡，且p75NTR（L401K）不能介导Aβ神经毒性。我们在百日咳毒素（PTX）存在的情况下转染对PTX耐药的G蛋白α亚基来分析细胞毒性途径，并确定Gαo蛋白而非Gαi蛋白参与p75NTR介导的Aβ神经毒性。进一步研究表明，通过p75NTR的Aβ神经毒性涉及JNK、NADPH氧化酶和半胱天冬酶-9/3，并受到活性依赖性神经营养因子、胰岛素样生长因子-I、碱性成纤维细胞生长因子和Humanin的抑制，这在原代神经元培养中也有观察到。了解Aβ神经毒性机制将对开发抗AD疗法有重大帮助。
