Shimohama S, Kihara T
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Biol Psychiatry. 2001 Feb 1;49(3):233-9. doi: 10.1016/s0006-3223(00)01100-8.
Multiple lines of evidence, from molecular and cellular to epidemiologic, have implicated nicotinic transmission in the pathology of Alzheimer's disease. In this review we present evidence for nicotinic receptor-mediated protection against beta-amyloid and glutamate neurotoxicity, and the signal transduction involved in this mechanism. The data are based mainly on our studies using rat-cultured primary neurons. Nicotine-induced protection was blocked by an alpha7 nicotinic receptor antagonist, a phosphatidylinositol 3-kinase inhibitor, and an Src inhibitor. Levels of phosphorylated Akt, an effector of phosphatidylinositol 3-kinase; Bcl-2; and Bcl-x were increased by nicotine administration. From these experimental data, our hypothesis for the mechanism of nicotinic receptor-mediated survival signal transduction is that the alpha7 nicotinic receptor stimulates the Src family, which activates phosphatidylinositol 3-kinase to phosphorylate Akt, which subsequently transmits the signal to upregulate Bcl-2 and Bcl-x. Upregulation of Bcl-2 and Bcl-x could prevent cells from neuronal death induced by beta-amyloid and glutamate. These findings suggest that an early diagnosis of Alzheimer's disease and protective therapy with nicotinic receptor stimulation could delay the progress of Alzheimer's disease.
从分子和细胞水平到流行病学，多方面的证据表明烟碱传递与阿尔茨海默病的病理过程有关。在本综述中，我们展示了烟碱受体介导的针对β-淀粉样蛋白和谷氨酸神经毒性的保护作用的证据，以及该机制中涉及的信号转导。这些数据主要基于我们使用大鼠原代培养神经元的研究。烟碱诱导的保护作用被α7烟碱受体拮抗剂、磷脂酰肌醇3-激酶抑制剂和Src抑制剂阻断。给予烟碱可增加磷脂酰肌醇3-激酶的效应器磷酸化Akt、Bcl-2和Bcl-x的水平。根据这些实验数据，我们关于烟碱受体介导的生存信号转导机制的假设是，α7烟碱受体刺激Src家族，后者激活磷脂酰肌醇3-激酶使Akt磷酸化，随后Akt将信号传递以上调Bcl-2和Bcl-x。Bcl-2和Bcl-x的上调可防止细胞因β-淀粉样蛋白和谷氨酸诱导的神经元死亡。这些发现表明，阿尔茨海默病的早期诊断以及烟碱受体刺激的保护性治疗可能会延缓阿尔茨海默病的进展。
