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Alzheimer’s disease (AD) is characterized by distinct tissue changes associated with accumulation of extracellular amyloid-beta (Aβ) peptides, and intracellular deposits of phosphorylated Tau (p-tau). There is a clear need to develop 3D AD model for alternative to animal test since current rodent model does not recapitulate complex human AD physiopathology. Here we report on organoid-grafted neurovascular unit (NUV) using 1) spheroid using APP-mutated neuro-progenitor cell and 2) endothelial-based blood brain barrier (BBB) against extracellular matrix. The construct was validated with AD pathology generation and further treatment with β- or γ-secretase inhibitors shows the decrease of Aβ. This paper demonstrates the potential utility of a membrane-free in vitro cortical spheroid tissue construct with BBB in a high throughput platform to model AD. 

Human induced pluripotent stem cell (hiPSC)-derived brain organoids can recapitulate the complex cytoarchitecture of the brain as well as the genetic and epigenetic footprint of human brain development. Although the brain organoids are able to mimic the structures and functions of brain in vitro, the 3D models have difficulty in integrating a complex vascular network that can provide the interaction with organoids. Here we report on a microfluidicbased three-dimensional, vascularized cortical organoid tissue construct consisting of 1) a perfused micro-vessel against an extracellular matrix (ECM), dynamic flow and membrane-free culture of the endothelial layer, 2) a sprouted vascular network using a combination of angiogenic factors, and 3) a vascularized hiPSCderived cortical organoid. We report on an optimization of density/stiffness of ECM to induce angiogenic sprouting and effect of angiogenic factors to trigger robust, rapid, and directional angiogenesis for concentration-driven and repetitive sprout formation. Vascularized network in the microfluidic device was further characterized in terms of morphology, directional alignment under perfusion, lumen formation, and permeability. HiPSCderived cortical organoid was generated, placed, and integrated into a vascularized network in the vascularized microfluidic device. We investigate how vascularized micro-vessels interact with cortical organoid. This paper further demonstrates the potential utility of a membrane-free vascularized cortical organoid in perfusion used to model Alzheimer’s disease and for toxicity screening of nerve agents.