Nat Med: In vitro reconstruction of human blood-brain barrier and study of APOE4 pathogenic mechanism

In Alzheimer's disease, amyloid protein deposits along brain blood vessels lead to a condition called brain amyloid vascular disease (CAA), which impairs the function of the blood-brain barrier (BBB) and accelerates cognitive degradationStudies have shown that lipoprotein 4 (APOE4) is the strongest risk factor for CAA, but the mechanism of this genetic susceptibility is not clearRecently, researchers developed a 3D model based on induced pluripotent stem cells, which reproduces the anatomical and physiological properties of human BBB in vitroSimilar to CAA, in this in vitro BBB model, significantly more amyloid protein accumulation was shown in APOE4 than in APOE3Combined experiments showed that the calcium protein-nucleic factor (NFAT) signal that activates T cells and the misalignment of APOE in surrounding cell-like wall cells induce APOE4-related CAA pathologyIn the human brain, APOE and NFAT are selectively misaligned in the surrounding cells of APOE4 carriersIn vitro and in vivo, inhibiting the transduction of calcium urea-NFAT signals can reduce the occurrence of APOE4-related CAA pathologyAs a result, the study revealed the role of cell circumference cells in APOE4-mediated CAA and highlighted the calcium nerve element-NFAT signal as a therapeutic target for CAA and Alzheimer's disease