Neuroinflammation is believed to play a primary role in the pathogenesis of most neurodegenerative diseases including Alzheimer’s disease, Parkinson’s and schizophrenia. Currently, suitable in vitro neuroinflammation models for studying cellular interactions and inflammatory mechanisms at the neurovascular unit are still scarce. In this study, we established an experimentally flexible tri-culture neuroinflammation model combining murine microglial cells (N11), neurons (N2A) and brain microvascular endothelial MVEC(B3) cells (MVEC) in a transwell co-culture system stimulated with lipopolysaccharides (LPS). Neuroinflammation was induced in this tri-culture model as manifested by activated N11 cells via toll-like receptor 4, resulting in increased release of proinflammatory mediators (nitric oxide, interleukin-6, and tumor necrosis factor-α) through the activation of nuclear factor-κB signaling pathways. The released inflammatory cytokines from N11 in turn, damaged the tight junction in MVEC cells, increased permeability of endothelial barrier, and induced Tau phosphorylation and upregulated caspase-3 expression in N2A cells, leading to neuroinflammation injury. In summary, this tri-culture inflammation model mimics the microenvironment, the cellular crosstalk and the molecular events that take place during neuroinflammation. It provides a robust in vitro model for studying neuroinflammation mechanisms and screening for potential therapeutic compounds or drugs candidates to treat various neurodegenerative diseases.
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