Human 3D Neuro-Vascular Interaction and Meningeal Lymphatic Models with Application to Alzheimer’s Disease

项目总结 随着老年人口的增加，阿尔茨海默病(AD)患者的数量正在迅速上升。那里 因此，人们对体外人类疾病模型的开发越来越感兴趣，以更好地理解和 研究阿尔茨海默病的生理和病理机制。新出现的证据表明， 阿尔茨海默病患者早期血脑屏障的破坏，甚至在认知功能下降和脑病理之前。此外, 脑膜淋巴管负责Aβ多肽从脑实质中的清除和破坏 AD转基因小鼠脑膜淋巴管的缺失加速Aβ在脑膜的沉积，加重 实质β积聚，并导致认知障碍。然而，我们对流体作用的理解 通过血脑屏障、脑实质和淋巴系统的转运很差。 明白了。因此，AD生理现实的神经细胞培养模型的建立 迫切需要神经血管单位和脑膜淋巴管来剖析分子机制。 研究阿尔茨海默病的致病级联反应，加速AD新药的发现。建立在我们的 广泛的初步研究和相关研究，我们建议建立一个三维(3D)的体外模型 通过整合血脑屏障、脑膜淋巴管和干细胞来源的AD细胞培养来接近模拟AD脑 环境。通过这个模型，我们的目标是确定AD的病理生理变化的特定机制 血脑屏障、脑膜淋巴管和β清除。我们的3D AD模型将不仅用于研究 这不仅有助于研究阿尔茨海默病的进展机制，也有助于在类人脑环境中进行药物发现。

PROJECT SUMMARY As the elderly population increases, the number of people with Alzheimer's disease (AD) is rising rapidly. There is, therefore, a growing interest in the development of in vitro human disease models to better understand and study the physiological and pathological mechanisms associated with AD. Emerging evidence has implicated an early breakdown of the BBB in AD patients, even before the cognitive decline and brain pathology. In addition, meningeal lymphatics are responsible for clearance of Aβ peptides from the brain parenchyma, and disruption of meningeal lymphatics in AD transgenic mice accelerates Aβ deposition in the meninges, aggravates parenchymal Aβ accumulation, and induces cognitive impairment. Yet, our understanding of the role of fluid transport across the BBB, through the brain parenchyma, and exiting via the lymphatic system is poorly understood. Therefore, the development of physiologically realistic human neural cell culture models of AD with a neurovascular unit and meningeal lymphatic vessels is urgently needed to dissect molecular mechanisms underlying the pathogenic cascade of AD and accelerate the discovery of new AD drugs. Building on our extensive set of preliminary and related studies, we propose to develop a three-dimensional (3D) in vitro model by integrating BBB, meningeal lymphatics, and stem-cell-derived AD cell culture to closely mimic the AD brain environment. With this model, we aim to identify AD-specific mechanisms underlying pathophysiological changes in the BBB, meningeal lymphatics, and Aβ clearance. Our 3D AD model will be useful for not only studying the mechanisms of AD progression but also for drug discovery in a human brain-like environment.