McCrea Liam T, Batorsky Rebecca E, Bowen Joshua J, Yeh Hana, Thanos Jessica M, Fu Ting, Perlis Roy H, Sheridan Steven D
Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Tufts Institute for Artificial Intelligence, Tufts University, Medford, MA, USA.
Neuropsychopharmacology. 2025 May 9. doi: 10.1038/s41386-025-02123-1.
Microglia dysregulation is implicated across a range of neurodevelopmental and neurodegenerative disorders, making their modulation a promising therapeutic target. Using PBMC-derived induced microglia-like cells (piMGLCs) in a scalable assay, we screened 489 CNS-penetrant compounds for modulation of microglial phagocytosis of human synaptosomes in a validated assay for microglia-mediated synaptic pruning. Compounds from the library that reduced phagocytosis by ≥2 standard deviations across the library without cytotoxicity were validated in secondary screens, with 28 of them further confirmed to reduce phagocytosis by 50% or more. These compounds comprise a wide range of therapeutic classes with different mechanisms of action, including immunosuppressants, kinase inhibitors, antipsychotics, and epigenetic modulators. Image-based morphological measurements were calculated to measure the degree of ramified vs. ameboid morphotypes as an indicator of activation state. Additionally, transcriptomic profiling indicated divergent effects on cell signaling, metabolism, activation, and actin dynamics across confirmed compounds. In particular, multiple CNS-penetrant small molecules with prior FDA approval or demonstration of safety in vivo demonstrated modulatory effects on microglia. For example, identified drugs such as the tyrosine kinase inhibitors lapatinib, alectinib, and lazertinib and the epigenetic modulator vorinostat have been approved for various cancer treatments and are being investigated for other indications; however, they have not been extensively studied in patients for neurodevelopmental and neurodegenerative disorders. These potential disease-modifying agents represent high-priority candidates for repositioning studies in neurodevelopmental, neuroinflammatory, or neurodegenerative disorders.
小胶质细胞功能失调与一系列神经发育和神经退行性疾病有关，这使得对其进行调节成为一个有前景的治疗靶点。我们在一个可扩展的实验中使用外周血单核细胞衍生的诱导性小胶质样细胞（piMGLCs），在一个经过验证的小胶质细胞介导的突触修剪实验中，筛选了489种可穿透中枢神经系统的化合物，以检测它们对人突触小体的小胶质细胞吞噬作用的调节。在二级筛选中验证了文库中那些在无细胞毒性的情况下使吞噬作用降低≥2个标准差的化合物，其中28种进一步被证实可使吞噬作用降低50%或更多。这些化合物包括具有不同作用机制的广泛治疗类别，包括免疫抑制剂、激酶抑制剂、抗精神病药物和表观遗传调节剂。通过基于图像的形态学测量来计算分支状与阿米巴样形态类型的程度，作为激活状态的指标。此外，转录组分析表明，已确认的化合物对细胞信号传导、代谢、激活和肌动蛋白动力学有不同的影响。特别是，多种先前已获得FDA批准或在体内证明安全的可穿透中枢神经系统的小分子对小胶质细胞有调节作用。例如，已鉴定出的药物如酪氨酸激酶抑制剂拉帕替尼、阿来替尼和拉泽替尼以及表观遗传调节剂伏立诺他已被批准用于各种癌症治疗，并且正在研究其他适应症；然而，它们尚未在患有神经发育和神经退行性疾病的患者中进行广泛研究。这些潜在的疾病修饰剂是神经发育、神经炎症或神经退行性疾病重新定位研究的高优先级候选药物。
