神经退行性变
载脂蛋白E
阿尔茨海默病
血脑屏障
神经科学
Cypa
发病机制
医学
病理
淀粉样蛋白(真菌学)
生物
疾病
亲环素A
中枢神经系统
分子生物学
作者
Axel Montagne,Angeliki M. Nikolakopoulou,Mikko T. Huuskonen,Abhay P. Sagare,Erica J. Lawson,Divna Lazić,Sanket Rege,Alexandra Grond,Edward Zúñiga,Samuel Barnes,Jacob Prince,Meghana Sagare,Ching-Ju Hsu,Mary Jo LaDu,Russell E. Jacobs,Berislav V. Zloković
出处
期刊:Nature Aging
日期:2021-06-14
卷期号:1 (6): 506-520
被引量:121
标识
DOI:10.1038/s43587-021-00073-z
摘要
Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer's disease (AD), leads to vascular dysfunction, amyloid-β pathology, neurodegeneration and dementia. How these different pathologies contribute to advanced-stage AD remains unclear. Using aged APOE knock-in mice crossed with 5xFAD mice, we show that, compared to APOE3, APOE4 accelerates blood-brain barrier (BBB) breakdown, loss of cerebral blood flow, neuronal loss and behavioral deficits independently of amyloid-β. BBB breakdown was associated with activation of the cyclophilin A-matrix metalloproteinase-9 BBB-degrading pathway in pericytes. Suppression of this pathway improved BBB integrity and prevented further neuronal loss and behavioral deficits in APOE4;5FAD mice while having no effect on amyloid-β pathology. Thus, APOE4 accelerates advanced-stage BBB breakdown and neurodegeneration in Alzheimer's mice via the cyclophilin A pathway in pericytes independently of amyloid-β, which has implication for the pathogenesis and treatment of vascular and neurodegenerative disorder in AD.
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