The glymphatic system, that is aquaporin 4 (AQP4) facilitated exchange of CSF with interstitial fluid (ISF), may provide a clearance pathway for protein species such as amyloid-β and tau, which accumulate in the brain in Alzheimer’s disease. Further, tau protein transference via the extracellular space, the compartment that is cleared by the glymphatic pathway, allows for its neuron-to-neuron propagation, and the regional progression of tauopathy in the disorder. The glymphatic system therefore represents an exciting new target for Alzheimer’s disease. Here we aim to understand the involvement of glymphatic CSF-ISF exchange in tau pathology. First, we demonstrate impaired CSF-ISF exchange and AQP4 polarization in a mouse model of tauopathy, suggesting that this clearance pathway may have the potential to exacerbate or even induce pathogenic accumulation of tau. Subsequently, we establish the central role of AQP4 in the glymphatic clearance of tau from the brain; showing marked impaired glymphatic CSF-ISF exchange and tau protein clearance using the novel AQP4 inhibitor, TGN-020. As such, we show that this system presents as a novel druggable target for the treatment of Alzheimer’s disease, and possibly other neurodegenerative diseases alike.

中文翻译：

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阿尔茨海默氏病模型中的淋巴功能和tau清除能力受损。

淋巴系统，即水通道蛋白4（AQP4）促进了脑脊液与组织液（ISF）的交换，可能为诸如淀粉样蛋白β和tau的蛋白质种类（在阿尔茨海默病的大脑中积聚）提供清除途径。此外，tau蛋白通过细胞外空间（通过淋巴途径清除的间隔）转移，使其神经元向神经元传播，并在该疾病中发生tauopathy的区域性进展。因此，淋巴系统代表了阿尔茨海默氏病令人兴奋的新靶标。在这里，我们旨在了解Tau病理中的淋巴性CSF-ISF交换的参与。首先，我们证明了tauopathy小鼠模型中CSF-ISF交换受损和AQP4极化，提示这种清除途径可能会加剧甚至诱导tau的致病性积累。随后，我们建立了AQP4在脑内tau的淋巴清除中的核心作用。显示使用新型AQP4抑制剂TGN-020显着削弱了淋巴性CSF-ISF交换和tau蛋白清除率。因此，我们表明该系统是治疗阿尔茨海默氏病以及其他可能的神经退行性疾病的新型药物靶标。