Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model.,Journal of Experimental Medicine

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Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model.
Journal of Experimental Medicine ( IF 12.6 ) Pub Date : 2019-10-10 , DOI: 10.1084/jem.20190980
Yang Shi ₁ , Melissa Manis ₁ , Justin Long ₁ , Kairuo Wang ₁ , Patrick M Sullivan ₂ , Javier Remolina Serrano ₁ , Rosa Hoyle ₁ , David M Holtzman ₃

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Chronic activation of brain innate immunity is a prominent feature of Alzheimer's disease (AD) and primary tauopathies. However, to what degree innate immunity contributes to neurodegeneration as compared with pathological protein-induced neurotoxicity, and the requirement of a particular glial cell type in neurodegeneration, are still unclear. Here we demonstrate that microglia-mediated damage, rather than pathological tau-induced direct neurotoxicity, is the leading force driving neurodegeneration in a tauopathy mouse model. Importantly, the progression of ptau pathology is also driven by microglia. In addition, we found that APOE, the strongest genetic risk factor for AD, regulates neurodegeneration predominantly by modulating microglial activation, although a minor role of apoE in regulating ptau and insoluble tau formation independent of its immunomodulatory function was also identified. Our results suggest that therapeutic strategies targeting microglia may represent an effective approach to prevent disease progression in the setting of tauopathy.

中文翻译：

小胶质细胞在tauopathy小鼠模型中驱动APOE依赖性神经变性。

大脑先天免疫的慢性激活是阿尔茨海默氏病（AD）和原发性tauopathies的突出特征。然而，与病理性蛋白质诱导的神经毒性相比，先天免疫在多大程度上有助于神经退行性变，以及神经退行性变中特定神经胶质细胞类型的要求尚不清楚。在这里，我们证明小胶质细胞介导的损伤，而不是病理性tau诱导的直接神经毒性，是驱动tauopathy小鼠模型中神经变性的主导力量。重要的是，小胶质细胞也驱动ptau病理学的发展。此外，我们发现APOE是AD的最强遗传危险因素，主要通过调节小胶质细胞激活来调节神经退行性病变，尽管还确定了apoE在调节ptau和不溶性tau的形成中具有较小的作用，而独立于其免疫调节功能。我们的结果表明，针对小胶质细胞的治疗策略可能代表了预防tauopathy疾病进展的有效方法。

更新日期：2019-11-04

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