SYK coordinates neuroprotective microglial responses in neurodegenerative disease [scRNA-seq]

Many neurodegenerative diseases are thought to be caused by impaired containment and/or disposal of neurotoxic material such as amyloid beta (Ab) and myelin debris. Indeed, recent human genome-wide association studies (GWAS) and animal model studies have begun to reveal critical roles for the brain’s professional phagocytes, microglia, as well as various innate immune receptors expressed by microglia in the control of neurotoxic material and subsequent neurodegenerative disease pathogenesis. Yet, the critical intracellular molecules that orchestrate the neuroprotective functions of microglia in degenerative disorders remain poorly understood. In our studies, we have identified the innate immune signaling molecule spleen tyrosine kinase (SYK) as a key regulator of microglial phagocytosis in neurodegenerative disease. We find that targeted deletion of SYK in microglia leads to exacerbated Ab deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer’s disease (AD). Furthermore, disruption of SYK signaling in this AD model was also shown to impede the development of disease-associated microglia (DAMs), alter AKT/GSK3b-signaling in microglia, and to cause severe deficits in the ability of microglia to phagocytose Ab. Importantly, these critical neuroprotective functions of SYK in microglia were not only restricted to Ab-driven models of neurodegeneration, as we found that SYK is also a critical regulator of microglial phagocytosis and DAM phenotype acquisition in demyelinating disease. Collectively, these results help to break new ground in our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material. Moreover, these findings suggest that targeting SYK may offer a therapeutic strategy to treat a spectrum of neurodegenerative disorders. Comparison of EAE severity and microglial response with or without SYK function. Using SYK +/+ pooled samples as baseline control to compare with SYK fl/fl microglia.

目前认为多种神经退行性疾病的致病机制与神经毒性物质（如β淀粉样蛋白（Ab）和髓鞘碎片）的捕获和/或清除功能受损密切相关。近年来，全基因组关联研究（GWAS）与动物模型研究逐渐揭示，大脑专职吞噬细胞——小胶质细胞，以及小胶质细胞表达的各类先天免疫受体，在调控神经毒性物质清除及后续神经退行性疾病发病进程中发挥关键作用。然而，在退行性疾病中协调小胶质细胞神经保护功能的关键细胞内分子仍有待阐明。
本研究鉴定出先天免疫信号分子脾酪氨酸激酶（SYK）是神经退行性疾病中小胶质细胞吞噬作用的核心调控因子。研究发现，在阿尔茨海默病（AD）的5xFAD小鼠模型中，特异性敲除小胶质细胞中的SYK会导致β淀粉样蛋白沉积加重、神经病理损伤加剧，并引发认知缺陷。
此外，在该AD模型中阻断SYK信号通路，还会阻碍疾病相关小胶质细胞（DAMs）的生成、改变小胶质细胞内AKT/GSK3β信号通路，并严重削弱小胶质细胞吞噬β淀粉样蛋白的能力。
值得注意的是，SYK在小胶质细胞中的这类关键神经保护功能并非仅局限于β淀粉样蛋白介导的神经退行性疾病模型：我们发现SYK同样是脱髓鞘疾病中小胶质细胞吞噬作用及疾病相关小胶质细胞表型获得的核心调控因子。
综上，本研究为阐明调控小胶质细胞响应神经毒性物质的有益功能的关键先天免疫信号分子开辟了新的研究方向。此外，上述研究结果提示，靶向SYK或可成为治疗一系列神经退行性疾病的治疗策略。
对比存在/缺失SYK功能时的实验性自身免疫性脑脊髓炎（EAE）严重程度与小胶质细胞应答反应。以SYK野生型（SYK+/+）混合样本作为基线对照，与SYK条件性敲除（SYKfl/fl）小胶质细胞进行比较。