<br>抑制CSF1R可缓解脑血管白质疾病和认知障碍,Glia

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抑制CSF1R可缓解脑血管白质疾病和认知障碍
Glia ( IF 5.4 ) Pub Date : 2023-11-01 , DOI: 10.1002/glia.24481
Katharine E Askew ₁ , Joshua Beverley ₁ , Emma Sigfridsson ₁ , Stefan Szymkowiak _{1,

2} , Katherine Emelianova _{1,

2} , Owen Dando _{1,

2} , Giles E Hardingham _{1,

2} , Jessica Duncombe ₁ , Edel Hennessy ₁ , Juraj Koudelka _{1,

2} , Neshika Samarasekera ₃ , Rustam Al-Shahi Salman ₃ , Colin Smith ₃ , Adriana A S Tavares ₄ , Diego Gomez-Nicola ₅ , Raj N Kalaria ₆ , Barry W McColl _{1,

2} , Karen Horsburgh ₁

Affiliation

与脑灌注不良相关的白质异常是小血管脑血管疾病的核心特征，也是血管性认知障碍和痴呆的关键决定因素。尽管如此重要，但仍缺乏治疗选择。在患者和动物模型中，小胶质细胞的增殖产生了扩大的反应性群体和相关的神经炎症改变，与脑血管白质疾病的发病和进展有关，这表明针对小胶质细胞增殖可能会发挥保护作用。集落刺激因子 1 受体 (CSF1R) 是小胶质细胞增殖的关键调节因子。我们发现，在人类脑血管疾病和临床相关的慢性脑灌注不足和血管性认知障碍的小鼠模型中，受损白质中CSF1R/Csf1r和其他表明小胶质细胞丰度增加的标志物的表达显着升高。使用小鼠模型，我们通过 GW2580 研究了长期药理学 CSF1R 抑制，并证明慢性低灌注白质中小胶质细胞数量的扩张被阻止。对低灌注白质组织的转录组分析显示小胶质细胞和炎症基因集的富集，包括吞噬细胞基因，这些基因是通过 CSF1R 抑制修饰的主要表达模块。此外，CSF1R 抑制减轻了低灌注引起的白质病理学，并挽救了空间学习障碍，并在较小程度上挽救了认知灵活性。总体而言，这项工作表明，抑制 CSF1R 和小胶质细胞增殖可以介导针对慢性脑血管白质病理和认知缺陷的保护作用。我们的研究提名 CSF1R 作为治疗血管性认知障碍的靶点，对其他慢性白质疾病的治疗具有更广泛的影响。

"点击查看英文标题和摘要"

Inhibiting CSF1R alleviates cerebrovascular white matter disease and cognitive impairment

White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.

更新日期：2023-11-01

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