Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, USA.
Waisman Center, University of Wisconsin-Madison, Madison, USA.
J Neuroinflammation. 2021 Mar 8;18(1):67. doi: 10.1186/s12974-021-02118-x.
Alexander disease (AxD) is a rare neurodegenerative disorder that is caused by dominant mutations in the gene encoding glial fibrillary acidic protein (GFAP), an intermediate filament that is primarily expressed by astrocytes. In AxD, mutant GFAP in combination with increased GFAP expression result in astrocyte dysfunction and the accumulation of Rosenthal fibers. A neuroinflammatory environment consisting primarily of macrophage lineage cells has been observed in AxD patients and mouse models.
To examine if macrophage lineage cells could serve as a therapeutic target in AxD, GFAP knock-in mutant AxD model mice were treated with a colony-stimulating factor 1 receptor (CSF1R) inhibitor, pexidartinib. The effects of pexidartinib treatment on disease phenotypes were assessed.
In AxD model mice, pexidartinib administration depleted macrophages in the CNS and caused elevation of GFAP transcript and protein levels with minimal impacts on other phenotypes including body weight, stress response activation, chemokine/cytokine expression, and T cell infiltration.
Together, these results highlight the complicated role that macrophages can play in neurological diseases and do not support the use of pexidartinib as a therapy for AxD.
亚历山大病（AxD）是一种罕见的神经退行性疾病，由编码胶质纤维酸性蛋白（GFAP）的基因突变引起，GFAP 是一种主要由星形胶质细胞表达的中间丝。在 AxD 中，突变型 GFAP 与 GFAP 表达增加相结合导致星形胶质细胞功能障碍和 Rosenthal 纤维的积累。在 AxD 患者和小鼠模型中观察到主要由巨噬细胞谱系细胞组成的神经炎症环境。
为了研究巨噬细胞谱系细胞是否可以作为 AxD 的治疗靶点，用集落刺激因子 1 受体（CSF1R）抑制剂培昔替尼处理 GFAP 敲入突变 AxD 模型小鼠。评估培昔替尼治疗对疾病表型的影响。
在 AxD 模型小鼠中，培昔替尼给药可耗尽中枢神经系统中的巨噬细胞，并导致 GFAP 转录物和蛋白水平升高，而对其他表型（包括体重、应激反应激活、趋化因子/细胞因子表达和 T 细胞浸润）的影响最小。
这些结果共同强调了巨噬细胞在神经疾病中可能发挥的复杂作用，并不支持使用培昔替尼作为 AxD 的治疗方法。
