小柯机器人

血脑屏障体外模型揭示APOE4致病机制
2020-06-11 11:49

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。

研究人员开发了一个基于诱导多能干细胞的三维模型,该模型概括了人类血脑屏障(BBB)在体外的解剖和生理特性。相比较于APOE3,研究人员的体外BBB在APOE4中显示出更多的淀粉样蛋白积累,并与脑淀粉样血管病(CAA)相似。
 
组合实验表明,钙调神经磷酸酶-NFAT(calcineurin–nuclear factor of activated T cells)信号和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APOE4相关的CAA病理。
 
这项研究揭示了周细胞在APOE4介导的CAA中的作用,并强调了钙调神经磷酸酶-NFAT信号是CAA和阿尔茨海默氏病的治疗靶标。
 
据了解,在阿尔茨海默氏病中,沿脑血管的淀粉样蛋白沉积会导致一种称为CAA的疾病,从而损害BBB功能并加速认知退化。APOE4是CAA的最高危险因素,但这种遗传易感性的潜在机制尚不清楚。
 
附:英文原文

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

分享到:

0