Molecular brain · 2026
Recapitulating Alzheimer's disease pathophysiology with a microfluidic neurospheroid-grafted endothelial barrier model.
СтатьяПоддержка NIH: внешняя программаПоддержка правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Uzoechi Samuel Chidiebere, Johnson-Campbell Charity, Badeaux Cody Joseph, Kwak Sang Su, Kim Doo Yeon, Yun Yeoheung
Аннотация
BACKGROUND: Traditional two-dimensional (2D) models do not adequately capture the complex cellular interactions, brain-specific architecture, and progressive pathology of Alzheimer's disease (AD). Three-dimensional (3D) organoid and microfluidic technologies provide more physiologically relevant platforms for studying AD-associated neurovascular dysfunction.
METHODS: We developed a membrane-free microfluidic endothelial barrier model integrated with neurospheroids derived from familial AD (FAD) neural progenitor cells. Human endothelial cells were cultured within perfusable microfluidic channels to establish a vascular-like interface rather than a fully specialized BBB endothelium. Pre-differentiated neurospheroids were grafted into the brain chamber. Endothelial barrier integrity, tight-junction expression, phosphorylated tau (pTau), and Aβ42/Aβ40 production and distribution between compartments were assessed using immunofluorescence imaging and ELISA.
RESULTS: The neurospheroid-grafted endothelial barrier construct captured key AD-associated phenotypes. ReN-AD-D4 models exhibited increased endothelial barrier permeability, reduced ZO-1 expression, and elevated pTau relative to controls. The platform supported endogenous Aβ generation, accumulation, and endothelial-associated deposition at the endothelial barrier. ELISA demonstrated differential Aβ42 and Aβ40 distribution, consistent with isoform-selective behavior reported in AD pathology. Collectively, these results indicate co-occurring neuronal and endothelial barrier alterations within the integrated 3D system.
CONCLUSION: This microfluidic endothelial barrier-neurospheroid platform enables quantitative assessment of amyloid-β accumulation, spatial distribution, and compartmentalized secretion alongside tau pathology and endothelial barrier integrity changes. Integrating human endothelial monolayers with FAD-derived neurospheroids, the system is scalable and compatible with high-content imaging. Although it does not model BBB-specific transport mechanisms, it provides a robust framework for hypothesis-driven studies of neurovascular interactions and therapeutic screening applications.
METHODS: We developed a membrane-free microfluidic endothelial barrier model integrated with neurospheroids derived from familial AD (FAD) neural progenitor cells. Human endothelial cells were cultured within perfusable microfluidic channels to establish a vascular-like interface rather than a fully specialized BBB endothelium. Pre-differentiated neurospheroids were grafted into the brain chamber. Endothelial barrier integrity, tight-junction expression, phosphorylated tau (pTau), and Aβ42/Aβ40 production and distribution between compartments were assessed using immunofluorescence imaging and ELISA.
RESULTS: The neurospheroid-grafted endothelial barrier construct captured key AD-associated phenotypes. ReN-AD-D4 models exhibited increased endothelial barrier permeability, reduced ZO-1 expression, and elevated pTau relative to controls. The platform supported endogenous Aβ generation, accumulation, and endothelial-associated deposition at the endothelial barrier. ELISA demonstrated differential Aβ42 and Aβ40 distribution, consistent with isoform-selective behavior reported in AD pathology. Collectively, these results indicate co-occurring neuronal and endothelial barrier alterations within the integrated 3D system.
CONCLUSION: This microfluidic endothelial barrier-neurospheroid platform enables quantitative assessment of amyloid-β accumulation, spatial distribution, and compartmentalized secretion alongside tau pathology and endothelial barrier integrity changes. Integrating human endothelial monolayers with FAD-derived neurospheroids, the system is scalable and compatible with high-content imaging. Although it does not model BBB-specific transport mechanisms, it provides a robust framework for hypothesis-driven studies of neurovascular interactions and therapeutic screening applications.