NFAT公司
脑淀粉样血管病
周细胞
壁细胞
血脑屏障
载脂蛋白E
诱导多能干细胞
钙调神经磷酸酶
老年斑
细胞生物学
生物
人脑
阿尔茨海默病
体外
神经科学
病理
癌症研究
医学
内皮干细胞
疾病
移植
中枢神经系统
内科学
胚胎干细胞
痴呆
基因
生物化学
作者
Joel Blanchard,Michael Bula,José Dávila-Velderrain,Leyla Anne Akay,Lena Zhu,Alexander Frank,Matheus B. Victor,Julia Maeve Bonner,Hansruedi Mathys,Yong Lin,Tak Ko,David A. Bennett,Hugh P. Cam,M Kellis,Li‐Huei Tsai
出处
期刊:Nature Medicine
[Springer Nature]
日期:2020-06-01
卷期号:26 (6): 952-963
被引量:158
标识
DOI:10.1038/s41591-020-0886-4
摘要
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. An iPSC-based three-dimensional model of the human blood–brain barrier reveals that NFAT and APOE dysregulation in pericyte-like mural cells contributes to cerebral amyloid angiopathy and can potentially be targeted to treat Alzheimer’s disease.
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