Link Andrea S, Zheng Fang, Alzheimer Christian
Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg Erlangen, Germany.
Front Mol Neurosci. 2016 May 10;9:32. doi: 10.3389/fnmol.2016.00032. eCollection 2016.
Activins are members of the transforming growth factor β (TGFβ) family and serve as multifunctional regulatory proteins in many tissues and organs. In the brain, activin A, which is formed by two disulfide-linked βA subunits, is recognized as the predominant player in activin signaling. Over the last years, considerable progress has been made in elucidating novel and unexpected functions of activin in the normal and diseased brain and in deciphering the underlying molecular mechanisms. Initially identified as a neurotrophic and protective factor during development and in several forms of acute injury, the scope of effects of activin A in the adult central nervous system (CNS) has been considerably broadened by now. Here, we will highlight recent findings that bear significance for a better understanding of the pathogenesis of various neuropsychiatric diseases and might hold promise for novel therapeutic strategies. While the basal level of activin A in the adult brain is low, significant short-term up-regulation occurs in response to increased neuronal activity. In fact, brief exposure to an enriched environment (EE) is already sufficient to considerably strengthen activin signaling. Enhancement of this pathway tunes the performance of glutamatergic and GABAergic synapses in a fashion that impacts on cognitive functions and affective behavior, counteracts death-inducing signals through extrasynaptic NMDA receptors (NMDARs), and stimulates adult neurogenesis in the hippocampus. We will discuss how impaired activin signaling is involved in anxiety disorders, depression, drug dependence, and neurodegenerative diseases such as Alzheimer's and Parkinson's, and how reinforcement of activin signaling might be exploited for therapeutic interventions.
激活素是转化生长因子β（TGFβ）家族的成员，在许多组织和器官中作为多功能调节蛋白发挥作用。在大脑中，由两个通过二硫键连接的βA亚基组成的激活素A被认为是激活素信号传导的主要参与者。在过去几年中，在阐明激活素在正常和患病大脑中的新功能和意外功能以及破译潜在分子机制方面取得了相当大的进展。激活素A最初被确定为发育过程中和几种急性损伤形式中的神经营养和保护因子，目前其在成体中枢神经系统（CNS）中的作用范围已大大拓宽。在这里，我们将重点介绍一些最新发现，这些发现对于更好地理解各种神经精神疾病的发病机制具有重要意义，并且可能为新的治疗策略带来希望。虽然成体大脑中激活素A的基础水平较低，但在神经元活动增加时会出现显著的短期上调。事实上，短暂暴露于丰富环境（EE）就足以显著增强激活素信号传导。该信号通路的增强以影响认知功能和情感行为的方式调节谷氨酸能和γ-氨基丁酸能突触的性能，通过突触外N-甲基-D-天冬氨酸受体（NMDARs）抵消死亡诱导信号，并刺激海马体中的成体神经发生。我们将讨论激活素信号传导受损如何参与焦虑症、抑郁症、药物依赖以及诸如阿尔茨海默病和帕金森病等神经退行性疾病，以及如何利用激活素信号传导的增强进行治疗干预。
