Abstract：
As a risk factor for Alzheimer\'s disease (AD), studies have demonstrated that long-term high-fat diet (HFD) could accelerate the deposition of amyloid beta (Aβ) in the brain. The glymphatic system plays a critical role in Aβ clearance from the brain. However, studies investigating the effects of long-term HFD on glymphatic function have reported paradoxical outcomes, and whether glymphatic dysfunction is involved in the disturbance of Aβ clearance in long-term HFD-fed mice has not been determined. In the present study, we injected fluorescently labeled Aβ into the hippocampus and found that Aβ clearance was decreased in HFD-fed mice. We found that long-term HFD-fed mice had decreased glymphatic function by injecting fluorescent tracers into the cisterna magna and corpus striatum. In long-term HFD-fed mice, aquaporin-4 (AQP4) polarization in the cortex was disrupted, and glymphatic clearance activity was positively correlated with the AQP4 polarization index. In HFD-fed mice, the disturbance of Aβ clearance from the hippocampus was exacerbated by TGN-020, a specific inhibitor of AQP4, whereas TGN-073, an enhancer of AQP4, ameliorated it. These findings suggest that long-term HFD disrupts Aβ clearance by inhibiting AQP4-mediated glymphatic function. The underlying mechanism may involve the disruption of AQP4 polarization.
摘要：
作为阿尔茨海默病（AD）的危险因素，研究表明，长期高脂饮食（HFD）可以加速β淀粉样蛋白（Aβ）在大脑中的沉积。淋巴系统在从大脑中清除Aβ中起关键作用。然而,调查长期HFD对类淋巴功能影响的研究报告了矛盾的结局，并且尚未确定长期HFD喂养的小鼠中的淋巴功能障碍是否与Aβ清除障碍有关。在本研究中,我们将荧光标记的Aβ注射到海马中，发现在HFD喂养的小鼠中Aβ清除率降低。我们发现，长期饲喂HFD的小鼠通过将荧光示踪剂注射到大脑池和纹状体中而降低了淋巴功能。在长期喂养HFD的小鼠中，水通道蛋白-4（AQP4）极化在皮质被破坏，而类淋巴清除活性与AQP4极化指数呈正相关。在HFD喂养的小鼠中，AQP4的特异性抑制剂TGN-020加剧了海马Aβ清除障碍，而AQP4的增强剂TGN-073则改善了海马Aβ清除障碍。这些发现表明，长期HFD通过抑制AQP4介导的淋巴功能来破坏Aβ清除。潜在的机制可能涉及AQP4极化的破坏。
