近日,美国麻省理工学院Li-Huei Tsai及其团队利用体外人血脑屏障的重建,揭示了周细胞中载脂蛋白E4(APOE4)的致病机制。该项研究成果于2020年6月8日在线发表在《自然—医学》杂志上。
Title: Reconstruction of the human blood–brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes
Author: Joel W. Blanchard, Michael Bula, Jose Davila-Velderrain, Leyla Anne Akay, Lena Zhu, Alexander Frank, Matheus B. Victor, Julia Maeve Bonner, Hansruedi Mathys, Yuan-Ta Lin, Tak Ko, David A. Bennett, Hugh P. Cam, Manolis Kellis, Li-Huei Tsai
Issue&Volume: 2020-06-08
Abstract: 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.
DOI: 10.1038/s41591-020-0886-4
Source: https://www.nature.com/articles/s41591-020-0886-4
Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:87.241
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex
本期文章:《自然—医学》:Online/在线发表