APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline

doi:10.1038/s41586-020-2247-3

GSTDTAP > 地球科学

DOI	10.1038/s41586-020-2247-3
	APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline
	Doherty, Tiarnan A. S.1; Winchester, Andrew J.2; Macpherson, Stuart 1; Johnstone, Duncan N.3; Pareek, Vivek 2; Tennyson, Elizabeth M.1; Kosar, Sofiia 2; Kosasih, Felix U.3; Anaya, Miguel 1; Abdi-Jalebi, Mojtaba 1,7; Andaji-Garmaroudi, Zahra 1; Wong, E. Laine 2; Madeo, Julien 2; Chiang, Yu-Hsien 1; Park, Ji-Sang 4,8; Jung, Young-Kwang 5; Petoukhoff, Christopher E.2; Divitini, Giorgio 3; Man, Michael K. L.2; Ducati, Caterina 3; Walsh, Aron 4,5; Midgley, Paul A.3; Dani, Keshav M.2; Stranks, Samuel D.1,6
	2020-04-16
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
卷号	581 期号:7806 页码:70-+
文章类型	Article
语种	英语
国家	USA; Australia
英文关键词	Breakdown of the blood-brain barrier in individuals carrying the epsilon 4 allele of the APOE gene, but not the epsilon 3 allele, increases with and predicts cognitive impairment and is independent of amyloid beta or tau pathology. Vascular contributions to dementia and Alzheimer' s disease are increasingly recognized(1-6). Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction(7), including the early clinical stages of Alzheimer' s disease(5,8-10). The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer' s disease(11-14), leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes(15-19), which maintain BBB integrity(20-22). It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the epsilon 3/epsilon 4 or epsilon 4/epsilon 4 alleles) are distinguished from those without APOE4 (epsilon 3/epsilon 3) 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-beta or tau pathology measured in cerebrospinal fluid or by positron emission tomography(23). High baseline levels of the BBB pericyte injury biomarker soluble PDGFR beta(7,8) in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-beta and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway(19) 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.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000529600400009
WOS关键词	HUMAN CEREBRAL-CORTEX ; DATA SET UDS ; ALZHEIMERS-DISEASE ; NEUROVASCULAR UNIT ; RISK-FACTORS ; PERICYTES ; BREAKDOWN ; GENOTYPE ; GENE ; TAU
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281207
专题	地球科学资源环境科学气候变化
作者单位	1.Univ Cambridge, Cavendish Lab, Cambridge, England; 2.Okinawa Inst Sci & Technol Grad Univ, Femtosecond Spect Unit, Onna Son, Japan; 3.Univ Cambridge, Dept Mat Sci & Met, Cambridge, England; 4.Imperial Coll London, Dept Mat, London, England; 5.Yonsei Univ, Dept Mat Sci & Engn, Seoul, South Korea; 6.Univ Cambridge, Dept Chem Engn & Biotechnol, Cambridge, England; 7.UCL, Inst Mat Discovery, London, England; 8.Kyungpook Natl Univ, Dept Phys, Daegu, South Korea
推荐引用方式 GB/T 7714	Doherty, Tiarnan A. S.,Winchester, Andrew J.,Macpherson, Stuart,et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline[J]. NATURE,2020,581(7806):70-+.
APA	Doherty, Tiarnan A. S..,Winchester, Andrew J..,Macpherson, Stuart.,Johnstone, Duncan N..,Pareek, Vivek.,...&Stranks, Samuel D..(2020).APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.NATURE,581(7806),70-+.
MLA	Doherty, Tiarnan A. S.,et al."APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline".NATURE 581.7806(2020):70-+.