Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Curr Alzheimer Res. 2012 Feb;9(2):227-40. doi: 10.2174/156720512799361600.
The Notch pathway is a critical mediator of short-range cell-cell communication that is reiteratively used to regulate a diverse array of cellular processes during embryonic development and the renewal and maintenance of adult tissues. Most Notch-dependent processes utilize a core signaling mechanism that is dependent on regulated intramembrane proteolysis: Upon ligand binding, Notch receptors undergo ectodomain shedding by ADAM metalloproteases, followed by γ-secretase-mediated intramembrane proteolysis. This releases the Notch intracellular domain, which translocates to the nucleus to activate transcription. In this review, we highlight the roles of Notch signaling particularly in self-renewing tissues in adults and several human diseases and raise some key considerations when targeting ADAMs and γ-secretase as disease-modifying strategies for Alzheimer's Disease.
Notch 通路是一种关键的短程细胞间通讯介质，反复用于调节胚胎发育过程以及成人组织的更新和维持过程中各种细胞过程。大多数依赖 Notch 的过程利用依赖于调节的跨膜蛋白水解的核心信号机制：配体结合后，Notch 受体通过 ADAM 金属蛋白酶进行胞外域脱落，随后进行 γ-分泌酶介导的跨膜蛋白水解。这会释放 Notch 细胞内结构域，该结构域易位到细胞核中以激活转录。在这篇综述中，我们特别强调了 Notch 信号在成人自我更新组织中的作用以及几种人类疾病，并在将 ADAMs 和 γ-分泌酶作为阿尔茨海默病的疾病修饰策略时提出了一些关键考虑因素。
