Alzheimer’s disease (AD) and dementia in general are age-related diseases with multiple contributing factors, including brain inflammation. Microglia, and specifically those expressing the AD risk gene TREM2, are considered important players in AD, but their exact contribution to pathology remains unclear. In this study, using high-throughput mass cytometry in the 5×FAD mouse model of amyloidosis, we identified senescent microglia that express high levels of TREM2 but also exhibit a distinct signature from TREM2-dependent disease-associated microglia (DAM). This senescent microglial protein signature was found in various mouse models that show cognitive decline, including aging, amyloidosis and tauopathy. TREM2-null mice had fewer microglia with a senescent signature. Treating 5×FAD mice with the senolytic BCL2 family inhibitor ABT-737 reduced senescent microglia, but not the DAM population, and this was accompanied by improved cognition and reduced brain inflammation. Our results suggest a dual and opposite involvement of TREM2 in microglial states, which must be considered when contemplating TREM2 as a therapeutic target in AD.

阿尔茨海默病 (AD) 和痴呆症一般都是与年龄相关的疾病，有多种影响因素，包括脑部炎症。小胶质细胞，特别是表达 AD 风险基因 TREM2 的小胶质细胞，被认为是 AD 的重要参与者，但它们对病理学的确切贡献仍不清楚。在这项研究中，我们在 5×FAD 淀粉样变性小鼠模型中使用高通量质谱流式细胞仪，鉴定出表达高水平 TREM2 的衰老小胶质细胞，但也表现出与 TREM2 依赖性疾病相关小胶质细胞 (DAM) 不同的特征。这种衰老的小胶质细胞蛋白特征在各种表现出认知能力下降的小鼠模型中被发现，包括衰老、淀粉样变性和 tau 蛋白病。 TREM2 缺失的小鼠具有较少的具有衰老特征的小胶质细胞。用 senolytic BCL2 家族抑制剂 ABT-737 治疗 5×FAD 小鼠可以减少衰老的小胶质细胞，但不能减少 DAM 群体，并且伴随着认知的改善和脑部炎症的减少。我们的结果表明 TREM2 在小胶质细胞状态中具有双重且相反的参与，在考虑将 TREM2 作为 AD 的治疗靶点时必须考虑这一点。