In Alzheimer’s disease, amyloid deposits along the brain vasculature lead to a condition known as cerebral amyloid angiopathy (CAA), which impairs blood–brain barrier (BBB) function and accelerates cognitive degeneration. Apolipoprotein (APOE4) is the strongest risk factor for CAA, yet the mechanisms underlying this genetic susceptibility are unknown. Here we developed an induced pluripotent stem cell-based three-dimensional model that recapitulates anatomical and physiological properties of the human BBB in vitro. Similarly to CAA, our in vitro BBB displayed significantly more amyloid accumulation in APOE4 compared to APOE3. Combinatorial experiments revealed that dysregulation of calcineurin–nuclear factor of activated T cells (NFAT) signaling and APOE in pericyte-like mural cells induces APOE4-associated CAA pathology. In the human brain, APOE and NFAT are selectively dysregulated in pericytes of APOE4 carriers, and inhibition of calcineurin–NFAT signaling reduces APOE4-associated CAA pathology in vitro and in vivo. Our study reveals the role of pericytes in APOE4-mediated CAA and highlights calcineurin–NFAT signaling as a therapeutic target in CAA and Alzheimer’s disease.

在阿尔茨海默氏病中，沿大脑血管系统沉积的淀粉样蛋白会导致一种称为脑淀粉样血管病（CAA）的疾病，从而损害血脑屏障（BBB）功能并加速认知退化。载脂蛋白（APO E4）是CAA的最强危险因素，但这种遗传易感性的潜在机制尚不清楚。在这里，我们开发了一个基于诱导多能干细胞的三维模型，该模型概括了人类BBB在体外的解剖和生理特性。与CAA相似，与APOE3相比，我们的体外BBB在APOE4中显示出更多的淀粉样蛋白积累。组合实验表明，钙调神经磷酸酶-活化T细胞（NFAT）信号转导的核因子和APOE在周细胞样壁细胞中的失调诱导了APOE4相关的CAA病理。在人脑中，APOE4携带者的周细胞中APOE和NFAT选择性失调，而钙调神经磷酸酶-NFAT信号的抑制作用可在体外和体内降低与APOE4相关的CAA病理。