Park Rena, Peng Yansong, Yslas Aria R, Lee Esak
Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York 14853, USA.
APL Bioeng. 2025 Jun 16;9(2):026126. doi: 10.1063/5.0261875. eCollection 2025 Jun.
The glymphatic system is a critical pathway for clearing metabolic waste from the brain by mediating cerebrospinal fluid and interstitial fluid exchange. In Alzheimer's disease (AD), tau protein accumulation is strongly associated with impaired glymphatic clearance, yet the underlying mechanism remains poorly defined. In this study, we employed a three-dimensional human glymphatics-on-chip model to investigate fluid transport and mass clearance in a brain-mimetic extracellular matrix containing engineered blood vessels (BV) surrounded by primary astrocytes. We found that phosphorylated tau (p-tau) induced morphological transformation of astrocytes into a hypertrophic, hypercontractile state, leading to astrocyte-mediated vasoconstriction and impaired glymphatic clearance. Notably, p-tau did not affect blood endothelial cells directly, implicating astrocyte-dependent mechanisms in glymphatic deregulation. Pharmacological inhibition of non-muscle myosin II with blebbistatin reversed astrocytic hypercontractility, restored BV diameters, and rescued glymphatic function. These findings elucidate a glial-specific mechanism of tau-induced glymphatic dysfunction and underscore astrocytic contractility as a promising therapeutic target in AD.
类淋巴系统是通过介导脑脊液和细胞间液交换来清除大脑代谢废物的关键途径。在阿尔茨海默病（AD）中，tau蛋白积累与类淋巴清除功能受损密切相关，但其潜在机制仍不清楚。在本研究中，我们采用三维人体类淋巴芯片模型，在含有工程化血管（BV）并被原代星形胶质细胞包围的脑模拟细胞外基质中研究液体运输和物质清除。我们发现，磷酸化tau（p-tau）诱导星形胶质细胞形态转变为肥大、高收缩状态，导致星形胶质细胞介导的血管收缩和类淋巴清除功能受损。值得注意的是，p-tau并不直接影响血管内皮细胞，提示类淋巴失调存在星形胶质细胞依赖机制。用blebbistatin对非肌肉肌球蛋白II进行药理学抑制可逆转星形胶质细胞的高收缩性，恢复BV直径，并挽救类淋巴功能。这些发现阐明了tau诱导类淋巴功能障碍的神经胶质特异性机制，并强调星形胶质细胞收缩性是AD中一个有前景的治疗靶点。
