UCL Centre for Advanced Biomedical Imaging, Department of Imaging, Division of Medicine, University College London, London, UK.
Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
Brain. 2020 Aug 1;143(8):2576-2593. doi: 10.1093/brain/awaa179.
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.
水通道蛋白 4（AQP4）介导的脑脊髓液（CSF）与细胞间液（ISF）交换的糖质淋系统，可能为阿尔茨海默病大脑中积累的淀粉样蛋白-β和 tau 等蛋白提供清除途径。此外，tau 蛋白通过细胞外空间（糖质淋系统清除的区域）转移，允许其在神经元间传播，从而导致 tau 病在该疾病中的区域性进展。因此，糖质淋系统是阿尔茨海默病的一个令人兴奋的新靶点。在这里，我们旨在了解糖质淋 CSF-ISF 交换在 tau 病理学中的作用。首先，我们在 tau 病的小鼠模型中证明了 CSF-ISF 交换和 AQP4 极化受损，表明这种清除途径可能有加剧甚至诱导 tau 致病积累的潜力。随后，我们确定了 AQP4 在 tau 从大脑中糖质淋清除中的核心作用；使用新型 AQP4 抑制剂 TGN-020，我们发现糖质淋 CSF-ISF 交换和 tau 蛋白清除明显受损。因此，我们表明该系统为阿尔茨海默病，甚至可能为其他神经退行性疾病的治疗提供了一个新的可药物治疗靶点。
