Disrupted blood-brain barrier in 5×FAD mouse model of Alzheimer's disease can be mimicked and repaired in vitro with neural stem cell-derived exosomes

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disease and is associated with blood-brain barrier (BBB) disruption. AD mice and cell culture models play an essential role in understanding AD pathogenesis and validation of therapeutic reagents. One of the commonly used AD mice is the 5 × FAD mouse and previous studies have shown that BBB leakage occurs at 9 months of age in the mice. However, it remains unknown whether disrupted BBB also occurs in young animals and whether AD-caused BBB impairment can be replicated and further corrected in a cell culture model. Here, we examine BBB breakdown in the 5 × FAD mouse model at different ages including both pre-symptomatic and post-symptomatic ages and test an in vitro BBB model established with the 5 × FAD primary cerebral endothelial cells. Moreover, with the BBB in vitro model, we also examined the therapeutic effect of human neural stem cells (NSCs)-derived exosomes on AD-caused BBB leakage. Our result indicated that BBB breakdown in the 5 × FAD mice occurred at 4 months of age, which could be mimicked with an in vitro BBB model. Importantly, we further demonstrated that treatment of the in vitro BBB model with NSCs-derived exosomes reversed AD-caused BBB deficiency. The information should be useful for researchers to determine which ages of the AD mice should be employed in specific in vivo and in vitro studies and the data also suggest that AD-caused BBB disruption can be corrected at least by NSC-derived exosomes.

Keywords: 5×FAD; Alzheimer’s disease; Blood-brain barrier; Exosomes; Neural stem cells; iPSC.