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研究揭示APOE4导致认知能力下降的机制
2020-04-30 20:21

美国南加州大学Berislav V. Zlokovic团队在研究中取得进展。他们发现载脂蛋白E(APOE4)导致血脑屏障(BBB)功能障碍,这可预示认知能力下降。相关论文于2020年4月29日在线发表于《自然》杂志。

研究人员发现携带APOE4(具有ε3/ε4或ε4/ε4等位基因)的个体与非携带(具有ε3/ε3)个体之间的区别在于海马和颞叶BBB的分解。这一发现在没有认知障碍的APOE4携带者中很明显,而在有认知障碍的携带者中则更为严重,但是这与通过脑脊液或正电子发射断层扫描所测得的淀粉样β或tau病理无关。

即使在控制了淀粉样β和tau水平后,脑脊液中BBB周细胞损伤的生物标志物可溶性PDGFRβ的高水平预示了APOE4携带者而非非携带者的未来认知能力下降,这与脑脊液中降解BBB的亲环蛋白A-基质金属蛋白酶9途径有关。

该研究结果表明,BBB的分解不依赖阿尔茨海默氏病的病理而导致与APOE4相关的认知功能下降,并且这可能作为APOE4携带者的治疗靶点 。

据悉,越来越多地研究表明血管对痴呆和阿尔茨海默氏病的重要作用。最近的研究表明,BBB的破坏是人类认知功能障碍的早期生物标志物,包括阿尔茨海默氏病的早期临床阶段。载脂蛋白E的E4变体是阿尔茨海默氏病的主要易感基因,导致BBB的加速分解和脑毛细血管周细胞的变性,脑毛细血管周细胞是保持BBB完整性所必需的。但是,尚不清楚APOE4的脑血管效应是否会导致认知障碍。

附:英文原文

Title: APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline

Author: Axel Montagne, Daniel A. Nation, Abhay P. Sagare, Giuseppe Barisano, Melanie D. Sweeney, Ararat Chakhoyan, Maricarmen Pachicano, Elizabeth Joe, Amy R. Nelson, Lina M. DOrazio, David P. Buennagel, Michael G. Harrington, Tammie L. S. Benzinger, Anne M. Fagan, John M. Ringman, Lon S. Schneider, John C. Morris, Eric M. Reiman, Richard J. Caselli, Helena C. Chui, Julia TCW, Yining Chen, Judy Pa, Peter S. Conti, Meng Law, Arthur W. Toga, Berislav V. Zlokovic

Issue&Volume: 2020-04-29

Abstract: Vascular contributions to dementia and Alzheimer’s disease are increasingly recognized1,2,3,4,5,6. Recent studies have suggested that breakdown of the blood–brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer’s disease5,8,9,10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer’s disease11,12,13,14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15,16,17,18,19, which maintain BBB integrity20,21,22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer’s disease pathology, and might be a therapeutic target in APOE4 carriers.

DOI: 10.1038/s41586-020-2247-3

Source: https://www.nature.com/articles/s41586-020-2247-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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