Interdisciplinary Program in Neuroscience, Seoul National University, Seoul 08826, Republic of Korea; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
Brain Behav Immun. 2024 Oct;121:291-302. doi: 10.1016/j.bbi.2024.08.002. Epub 2024 Aug 2.
In Alzheimer's disease, chronic neuroinflammation is accompanied by amyloid and tau pathologies. Especially, aberrant microglial activation is known to precede the regional tau pathology development, but the mechanisms how microglia affect tau spread remain largely unknown. Here, we found that toll-like receptor 2 (TLR2) in microglia recognizes oligomeric tau as a pathogenic ligand and induces inflammatory responses. Knockout of TLR2 reduced tau pathology and microglial activation in rTg4510 tau transgenic mice. Treatment of oligomeric tau induced TLR2 activation and increased inflammatory responses in microglial cells. TLR2 further mediated the tau-induced microglial activation and promoted tau uptake into neurons in neuron-microglia co-culture system and in mouse hippocampus after intracranial tau injection. Importantly, treatment with anti-TLR2 monoclonal antibody Tomaralimab blocked TLR2 activation and inflammatory responses in a dose-dependent manner, and significantly reduced tau spread and memory loss in rTg4510 mice. These results suggest that TLR2 plays a crucial role in tau spread by causing aberrant microglial activation in response to pathological tau, and blocking TLR2 with immunotherapy may ameliorate tau pathogenesis in Alzheimer's disease.
在阿尔茨海默病中，慢性神经炎症伴随着淀粉样蛋白和 tau 病理学。特别是，异常的小胶质细胞激活被认为先于区域性 tau 病理学的发展，但小胶质细胞如何影响 tau 传播的机制在很大程度上仍然未知。在这里，我们发现小胶质细胞中的 toll 样受体 2 (TLR2) 识别寡聚 tau 作为一种致病配体，并诱导炎症反应。TLR2 的敲除减少了 rTg4510 tau 转基因小鼠中的 tau 病理学和小胶质细胞激活。寡聚 tau 诱导 TLR2 激活并增加小胶质细胞中的炎症反应。TLR2 进一步介导 tau 诱导的小胶质细胞激活，并促进 tau 在神经元-小胶质细胞共培养系统和tau 颅内注射后小鼠海马中的摄取。重要的是，用抗 TLR2 单克隆抗体 Tomaralimab 进行治疗以剂量依赖性方式阻断 TLR2 的激活和炎症反应，显著减少了 rTg4510 小鼠中的 tau 传播和记忆丧失。这些结果表明，TLR2 通过对病理性 tau 做出异常的小胶质细胞激活反应，在 tau 传播中发挥关键作用，用免疫疗法阻断 TLR2 可能改善阿尔茨海默病中的 tau 发病机制。
