02641nas a2200349   4500000000100000000000100001008004100002260001500043653002900058653003000087653001800117653003600135653001700171100002200188700001600210700003200226700001900258700001300277700002000290700001500310700001500325700002300340700001600363700001700379700002100396700001800417245015300435856011500588490000700703520156700710022001402277       2023                            d  c2023-10-0910aAlzheimer's disease (AD)10ablood-brain barrier (BBB)10amicrofluidics10amicrophysiological system (MPS)10aneurospheres1 aEunkyung Clare Ko1 aSarah Spitz1 aFrancesca Michela Pramotton1 aOlivia M. Barr1 aCiana Xu1 aGeorgios Pavlou1 aShun Zhang1 aAlice Tsai1 aAnna Maaser-Hecker1 aMehdi Jorfi1 aSe Hoon Choi1 aRudolph E. Tanzi1 aRoger D. Kamm00aAccelerating the in vitro emulation of Alzheimer’s disease-associated phenotypes using a novel 3D blood-brain barrier neurosphere co-culture model  uhttps://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2023.1251195/full0 v113 a<p>High failure rates in clinical trials for neurodegenerative disorders such as Alzheimer’s disease have been linked to an insufficient predictive validity of current animal-based disease models. This has created an increasing demand for alternative, human-based models capable of emulating key pathological phenotypes <italic>in vitro</italic>. Here, a three-dimensional Alzheimer’s disease model was developed using a compartmentalized microfluidic device that combines a self-assembled microvascular network of the human blood-brain barrier with neurospheres derived from Alzheimer’s disease-specific neural progenitor cells. To shorten microfluidic co-culture times, neurospheres were pre-differentiated for 21 days to express Alzheimer’s disease-specific pathological phenotypes prior to the introduction into the microfluidic device. In agreement with post-mortem studies and Alzheimer’s disease <italic>in vivo</italic> models, after 7 days of co-culture with pre-differentiated Alzheimer’s disease-specific neurospheres, the three-dimensional blood-brain barrier network exhibited significant changes in barrier permeability and morphology. Furthermore, vascular networks in co-culture with Alzheimer’s disease-specific microtissues displayed localized β-amyloid deposition. Thus, by interconnecting a microvascular network of the blood-brain barrier with pre-differentiated neurospheres the presented model holds immense potential for replicating key neurovascular phenotypes of neurodegenerative disorders <italic>in vitro</italic>.</p>  a2296-4185