Le L H D, O'Banion M K, Majewska A K
Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY, USA.
Center for Visual Science, University of Rochester, Rochester, NY, USA.
Sci Rep. 2024 Dec 28;14(1):30912. doi: 10.1038/s41598-024-81910-0.
Colony-stimulating factor-1-receptor (CSF1R) inhibitors have been widely used to rapidly deplete microglia from the brain, allowing the remaining microglia population to self-renew and repopulate. These new-born microglia are thought to be "rejuvenated" and have been shown to be beneficial in several disease contexts and in normal aging. Their role in Alzheimer's disease (AD) is thus of great interest as they represent a potential disease-modifying therapy. Here, we explored the differential effects of microglial depletion and repopulation during amyloid pathology progression using 5xFAD mice. We utilized the CSF1R inhibitor PLX3397 to induce microglial self-renewal and tracked microglia-plaque dynamics with in vivo imaging. We observed transient improvement in plaque burden on different timescales depending on the animal's age. While the improvement in plaque burden did not persist in any age group, renewing microglia during mid- to late-pathology might still be beneficial as we observed a potential improvement in microglial sensitivity to noradrenergic signaling. Altogether, our findings provide further insights into the therapeutic potential of microglial renewal in AD.
集落刺激因子-1受体（CSF1R）抑制剂已被广泛用于快速清除大脑中的小胶质细胞，使剩余的小胶质细胞群体能够自我更新和重新填充。这些新生的小胶质细胞被认为是“年轻化的”，并且已被证明在多种疾病背景和正常衰老过程中具有益处。因此，它们在阿尔茨海默病（AD）中的作用备受关注，因为它们代表了一种潜在的疾病修饰疗法。在这里，我们使用5xFAD小鼠探讨了在淀粉样病理进展过程中小胶质细胞耗竭和重新填充的不同影响。我们利用CSF1R抑制剂PLX3397诱导小胶质细胞自我更新，并通过体内成像追踪小胶质细胞与斑块的动态变化。我们观察到，根据动物年龄的不同，斑块负担在不同时间尺度上出现了短暂改善。虽然斑块负担的改善在任何年龄组中都没有持续，但在病理中期至后期更新小胶质细胞可能仍然有益，因为我们观察到小胶质细胞对去甲肾上腺素能信号的敏感性有潜在改善。总之，我们的研究结果为小胶质细胞更新在AD中的治疗潜力提供了进一步的见解。
