Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular, Porto, Portugal.
Instituto de Farmacologia e Neurociências, Lisboa, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
Cell Rep. 2020 Jun 23;31(12):107796. doi: 10.1016/j.celrep.2020.107796.
Nervous tissue homeostasis requires the regulation of microglia activity. Using conditional gene targeting in mice, we demonstrate that genetic ablation of the small GTPase Rhoa in adult microglia is sufficient to trigger spontaneous microglia activation, producing a neurological phenotype (including synapse and neuron loss, impairment of long-term potentiation [LTP], formation of β-amyloid plaques, and memory deficits). Mechanistically, loss of Rhoa in microglia triggers Src activation and Src-mediated tumor necrosis factor (TNF) production, leading to excitotoxic glutamate secretion. Inhibiting Src in microglia Rhoa-deficient mice attenuates microglia dysregulation and the ensuing neurological phenotype. We also find that the Rhoa/Src signaling pathway is disrupted in microglia of the APP/PS1 mouse model of Alzheimer disease and that low doses of Aβ oligomers trigger microglia neurotoxic polarization through the disruption of Rhoa-to-Src signaling. Overall, our results indicate that disturbing Rho GTPase signaling in microglia can directly cause neurodegeneration.
神经组织的内稳态需要调节小胶质细胞的活性。通过在小鼠中进行条件性基因靶向，我们证明成年小胶质细胞中小 GTPase Rhoa 的基因缺失足以引发自发性小胶质细胞激活，产生神经病变表型（包括突触和神经元丢失、长时程增强 [LTP] 受损、β-淀粉样斑块形成和记忆缺陷）。从机制上讲，小胶质细胞中 Rhoa 的缺失会触发Src 的激活和 Src 介导的肿瘤坏死因子（TNF）的产生，导致兴奋性谷氨酸的释放。抑制小胶质细胞中的Src 可减轻 Rhoa 缺陷型小鼠中小胶质细胞的失调和随后的神经病变表型。我们还发现，阿尔茨海默病 APP/PS1 小鼠模型中小胶质细胞中的 Rhoa/Src 信号通路被破坏，并且低剂量的 Aβ 寡聚体通过破坏 Rhoa 到 Src 的信号转导引发小胶质细胞的神经毒性极化。总体而言，我们的结果表明，扰乱小胶质细胞中的 Rho GTPase 信号可以直接导致神经退行性变。
