期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 40, 期 1, 页码 128-144出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.119.313169
关键词
Alzheimer disease; blood-brain barrier; collagen IV; extracellular matrix; pericytes; risk factors; tight junction
资金
- National Institutes of Health (NIH) [RF1AG051504, P50AG016574, R37AG027924, R01AG035355, R01AG046205, R01AG051574]
- Cure Alzheimer's Fund
- American Heart Association [15SDG22460003]
- Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Program [7AZ22]
- Japan Society for the Promotion of Science (JSPS)
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
Objective: The epsilon 4 allele of the APOE gene (APOE4) is the strongest genetic risk factor for Alzheimer disease when compared with the common epsilon 3 allele. Although there has been significant progress in understanding how apoE4 (apolipoprotein E4) drives amyloid pathology, its effects on amyloid-independent pathways, in particular cerebrovascular integrity and function, are less clear. Approach and Results: Here, we show that brain pericytes, the mural cells of the capillary walls, differentially modulate endothelial cell phenotype in an apoE isoform-dependent manner. Extracellular matrix protein induction, tube-like structure formation, and barrier formation were lower with endothelial cells cocultured with pericytes isolated from apoE4-targeted replacement (TR) mice compared with those from apoE3-TR mice. Importantly, aged apoE4-targeted replacement mice had decreased extracellular matrix protein expression and increased plasma protein leakages compared with apoE3-TR mice. Conclusions: ApoE4 impairs pericyte-mediated basement membrane formation, potentially contributing to the cerebrovascular effects of apoE4.
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