Dagher Nabil N, Najafi Allison R, Kayala Kara M Neely, Elmore Monica R P, White Terra E, Medeiros Rodrigo, West Brian L, Green Kim N
Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, 3208 Biological Sciences III, Irvine, CA, 92697-4545, USA.
Plexxikon Inc., Berkeley, CA, USA.
J Neuroinflammation. 2015 Aug 1;12:139. doi: 10.1186/s12974-015-0366-9.
Microglia are dependent upon colony-stimulating factor 1 receptor (CSF1R) signaling for their survival in the adult brain, with administration of the dual CSF1R/c-kit inhibitor PLX3397 leading to the near-complete elimination of all microglia brainwide. Here, we determined the dose-dependent effects of a specific CSF1R inhibitor (PLX5622) on microglia in both wild-type and the 3xTg-AD mouse model of Alzheimer's disease.
Wild-type mice were treated with PLX5622 for up to 21 days, and the effects on microglial numbers were assessed. 3xTg-AD mice were treated with PLX5622 for 6 or 12 weeks and effects on microglial numbers and pathology subsequently assessed.
High doses of CSF1R inhibitor eliminate most microglia from the brain, but a 75% lower-dose results in sustained elimination of ~30 of microglia in both wild-type and 3xTg-AD mice. No behavioral or cognitive deficits were found in mice either depleted of microglia or treated with lower CSF1R inhibitor concentrations. Aged 3xTg-AD mice treated for 6 or 12 weeks with lower levels of PLX5622 resulted in improved learning and memory. Aβ levels and plaque loads were not altered, but microglia in treated mice no longer associated with plaques, revealing a role for the CSF1R in the microglial reaction to plaques, as well as in mediating cognitive deficits.
We find that inhibition of CSF1R alone is sufficient to eliminate microglia and that sustained microglial elimination is concentration-dependent. Inhibition of the CSF1R at lower levels in 3xTg-AD mice prevents microglial association with plaques and improves cognition.
成年大脑中的小胶质细胞依赖集落刺激因子1受体（CSF1R）信号来维持存活，给予双靶点CSF1R/c-kit抑制剂PLX3397可导致全脑几乎所有小胶质细胞被完全清除。在此，我们确定了特异性CSF1R抑制剂（PLX5622）对野生型和阿尔茨海默病3xTg-AD小鼠模型中小胶质细胞的剂量依赖性影响。
用PLX5622处理野生型小鼠长达21天，并评估对小胶质细胞数量的影响。用PLX5622处理3xTg-AD小鼠6周或12周，随后评估对小胶质细胞数量和病理学的影响。
高剂量的CSF1R抑制剂可清除大脑中的大部分小胶质细胞，但低75%的剂量可使野生型和3xTg-AD小鼠中约30%的小胶质细胞持续被清除。在小胶质细胞缺失或用较低浓度CSF1R抑制剂处理的小鼠中未发现行为或认知缺陷。用较低水平的PLX5622处理6周或12周的老年3xTg-AD小鼠，其学习和记忆能力得到改善。β淀粉样蛋白（Aβ）水平和斑块负荷未改变，但经处理小鼠中的小胶质细胞不再与斑块相关，这揭示了CSF1R在小胶质细胞对斑块的反应以及介导认知缺陷中的作用。
我们发现单独抑制CSF1R足以清除小胶质细胞，且小胶质细胞的持续清除具有浓度依赖性。在3xTg-AD小鼠中以较低水平抑制CSF1R可防止小胶质细胞与斑块相关并改善认知。
