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阿尔茨海默病(AD)是一种与年龄相关的神经退行性疾病，是痴呆症最常见的病因。AD的主要特征是神经原纤维缠结、异常淀粉样蛋白(A)聚集、神经炎症和神经元丢失;总体表现为认知能力的渐进性下降。人们曾多次尝试通过直接针对这些因素来阻止或减缓疾病进展，但在对认知产生有意义的影响方面取得的成功有限。近年来，AD的研究重点已扩展到局部和全身免疫反应的探索。然而，中枢神经系统(CNS)驻留免疫细胞、小胶质细胞和血液中单核细胞来源的巨噬细胞(MDM)这两个主要的髓系群体的作用尚不清楚。在读博士期间，我们与团队成员一起，利用行为学、免疫学、生化和单细胞分辨分子技术，破译了小胶质细胞和MDM在AD病理转基因小鼠模型中的独特作用。在5xFAD淀粉样变小鼠模型中，使用单细胞RNA测序(scRNA-seq)，我们发现了一种新的小胶质细胞状态，我们将其命名为疾病相关小胶质细胞(DAM)，发现它与a斑块非常接近。这些细胞的完全激活依赖于髓系细胞上表达的触发受体2 (TREM2)，这是一个众所周知的晚发AD的危险因素。获得洞察力MDM相对于小胶质细胞的作用,我们用一个实验范式的小幅增加的系统性免疫阻断抑制免疫途径检查站,PD-1 / PD-L1,以前是有益的在改善广告5 xfad小鼠,通过促进归航的MDM到大脑。 We found that the same treatment is efficient also in mouse model of tauopathy and that the MDM homing to the brain following the treatment expressed a unique set of scavenger molecules, including macrophage scavenger receptor 1 (MSR1). We found that MDM expressing MSR1 are essential for the disease modification. Using the same immune-modulatory treatment in a mouse model deficient in TREM2 (Trem2-/-5xFAD) and thus in DAM, allowed us to distinguish between the contribution to the disease modification of MDM and DAM. We found, that MDM display a Trem2-independent role in the cognitive improvement. In both Trem2-/-5xFAD and Trem2+/+5xFAD mice the treatment effect on behavior was accompanied by a reduction in the levels of hippocampal water-soluble Aβ1-42, a fraction of A that contains toxic oligomers. In Trem2+/+5xFAD mice, the same treatment seemed to activate additional Trem2-dependent mechanism, that could involve facilitation of removal of Aβ plaques by DAM or by other TREM2-expressing microglia. Collectively, our finding demonstrates the distinct role of activated microglia and MDM in therapeutic mechanism of AD pathology. They also support the approach of empowering the immune system to facilitate MDM mobilization as a common mechanism for treating AD, regardless of primary disease etiology and TREM2 genetic polymorphism.