小柯机器人

美国弗吉尼亚大学John R. Lukens课题组发现，SYK协调神经退行性疾病中的神经保护性小胶质细胞反应。相关论文于2022年10月17日在线发表于国际学术期刊《细胞》。

研究人员发现，在5xFAD阿尔茨海默病（AD）小鼠模型中，小胶质细胞中SYK的定向缺失会导致Aβ沉积加剧，神经病理学加重，以及认知缺陷。在这个AD模型中，SYK信号的中断被进一步证明阻碍了疾病相关小胶质细胞（DAM）的发展，改变了AKT/GSK3β信号，并限制了小胶质细胞的淀粉样蛋白β（Aβ）吞噬作用。相反，受体介导的SYK的激活限制了Aβ的负荷。研究人员还发现，SYK在脱髓鞘疾病中关键性地调节小胶质细胞的吞噬作用和DAM的获得。总之，这些结果扩大了人们对指导小胶质细胞对神经毒性物质，作出有益功能的关键先天免疫信号分子的理解。

据介绍，最近的研究已经开始揭示大脑的专业吞噬细胞、小胶质细胞及其受体，在控制神经退行性疾病中的神经毒性Aβ和髓鞘碎片积累中的关键作用。然而，协调小胶质细胞的神经保护功能的关键细胞内分子仍然知之甚少。

附：英文原文

Title: SYK coordinates neuroprotective microglial responses in neurodegenerative disease

Author: Hannah Ennerfelt, Elizabeth L. Frost, Daniel A. Shapiro, Coco Holliday, Kristine E. Zengeler, Gabrielle Voithofer, Ashley C. Bolte, Catherine R. Lammert, Joshua A. Kulas, Tyler K. Ulland, John R. Lukens

Issue&Volume: 2022-10-17

Abstract: Recent studies have begun to reveal critical roles for the brain’s professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aβ) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted deletion of SYK in microglia leads to exacerbated Aβ deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer’s disease (AD). Disruption of SYK signaling in this AD model was further shown to impede the development of disease-associated microglia (DAM), alter AKT/GSK3β-signaling, and restrict Aβ phagocytosis by microglia. Conversely, receptor-mediated activation of SYK limits Aβ load. We also found that SYK critically regulates microglial phagocytosis and DAM acquisition in demyelinating disease. Collectively, these results broaden our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material.

DOI: 10.1016/j.cell.2022.09.030

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)01249-1