SYK coordinates neuroprotective microglial responses in neurodegenerative disease.
SYK coordinates neuroprotective microglial responses in neurodegenerative disease.
复制标题
DOI：
10.1016/j.cell.2022.09.030
复制
发表时间：
2022-10-27
期刊：
影响因子：
64.5
通讯作者：
Lukens, John R.
中科院分区：
文献类型：
--
作者：
Ennerfelt, Hannah;Frost, Elizabeth L.;Shapiro, Daniel A.;Holliday, Coco;Zengeler, Kristine E.;Voithofer, Gabrielle;Bolte, Ashley C.;Lammert, Catherine R.;Kulas, Joshua A.;Ulland, Tyler K.;Lukens, John R.
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神经退行性疾病中控制神经毒性淀粉样蛋白（Aβ）和髓磷脂碎片积累的关键作用。然而，协调小胶质细胞神经保护功能的关键细胞内分子仍然知之甚少。在我们的研究中，我们发现小胶质细胞中SYK的靶向缺失导致阿尔茨海默病（AD） 5xFAD小鼠模型中Aβ沉积加剧，神经病理学加重和认知缺陷。在该AD模型中，SYK信号的破坏进一步被证明可以阻碍疾病相关小胶质细胞（DAM）的发展，改变AKT/ gsk3 β信号，并限制小胶质细胞对Aβ的吞噬。相反，受体介导的SYK激活限制了Aβ的负荷。我们还发现SYK在脱髓鞘疾病中对小胶质细胞吞噬和DAM获取起到关键调节作用。总的来说，这些结果扩大了我们对关键先天免疫信号分子的理解，这些信号分子指导有益的小胶质细胞功能对神经毒性物质作出反应。SYK是小胶质细胞活化和吞噬的中枢细胞内调节剂，用于限制a β病理和脱髓鞘疾病。
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. SYK is a central intracellular regulator of microglial activation and phagocytosis that is deployed to limit Aβ pathology and demyelinating disease.
登录
查看更多内容
影响因子：
9.3
作者：
Hadas S;Spira M;Hanisch UK;Reichert F;Rotshenker S
通讯作者：
Rotshenker S
影响因子：
4.7
作者：
Chung, Yeon-Ho;Kim, Hee Young;Lee, Won-Woo
通讯作者：
Lee, Won-Woo
影响因子：
9.3
作者：
Chu E;Mychasiuk R;Hibbs ML;Semple BD
通讯作者：
Semple BD
影响因子：
15.1
作者：
Bemiller SM;McCray TJ;Allan K;Formica SV;Xu G;Wilson G;Kokiko-Cochran ON;Crish SD;Lasagna-Reeves CA;Ransohoff RM;Landreth GE;Lamb BT
通讯作者：
Lamb BT
影响因子：
5.3
作者：
Gudi V;Gingele S;Skripuletz T;Stangel M
通讯作者：
Stangel M