Intracerebral GM-CSF contributes to transendothelial monocyte migration in APP/PS1 Alzheimer's disease mice

被引：41

作者：

Shang, De S. ^{[1
]}

Yang, Yi M. ^{[1
]}

Zhang, Hu ^{[1
]}

Tian, Li ^{[1
]}

Jiang, Jiu S. ^{[1
]}

Dong, Yan B. ^{[1
]}

Zhang, Ke ^{[1
]}

Li, Bo ^{[1
]}

Zhao, Wei D. ^{[1
]}

Fang, Wen G. ^{[1
]}

Chen, Yu H. ^{[1
]}

机构：

[1] China Med Univ, Minist Educ, Key Lab Med Cell Biol, Minist Publ Hlth,Key Lab Cell Biol,Dept Dev Cell, Shenyang, Peoples R China

来源：

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM | 2016年 / 36卷 / 11期

基金：

中国国家自然科学基金; 高等学校博士学科点专项科研基金;

关键词：

Alzheimer's disease; CSF2RB; granulocyte-macrophage colony-stimulating factor; monocyte infiltration; BLOOD-BRAIN-BARRIER; COLONY-STIMULATING FACTOR; MICROVASCULAR ENDOTHELIAL-CELLS; TIGHT JUNCTION PROTEINS; CENTRAL-NERVOUS-SYSTEM; HIGH-AFFINITY BINDING; AMYLOID-BETA PEPTIDE; MICROGLIAL CELLS; STEM-CELLS; EXPRESSION;

D O I：

10.1177/0271678X16660983

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Although tight junctions between human brain microvascular endothelial cells in the blood-brain barrier prevent molecules or cells in the bloodstream from entering the brain, in Alzheimer's disease, peripheral blood monocytes can open these tight junctions and trigger subsequent transendothelial migration. However, the mechanism underlying this migration is unclear. Here, we found that the CSF2RB, but not CSF2RA, subunit of the granulocyte-macrophage colony-stimulating factor receptor was overexpressed on monocytes from Alzheimer's disease patients. CSF2RB contributes to granulocyte-macrophage colony-stimulating factor-induced transendothelial monocyte migration. Granulocyte-macrophage colony-stimulating factor triggers human brain microvascular endothelial cells monolayer tight junction disassembly by downregulating ZO-1 expression via transcription modulation and claudin-5 expression via the ubiquitination pathway. Interestingly, intracerebral granulocyte-macrophage colony-stimulating factor blockade abolished the increased monocyte infiltration in the brains of APP/PS1 Alzheimer's disease model mice. Our results suggest that in Alzheimer's disease patients, high granulocyte-macrophage colony-stimulating factor levels in the brain parenchyma and cerebrospinal fluid induced blood-brain barrier opening, facilitating the infiltration of CSF2RB-expressing peripheral monocytes across blood-brain barrier and into the brain. CSF2RB might be useful as an Alzheimer's disease biomarker. Thus, our findings will help to understand the mechanism of monocyte infiltration in Alzheimer's disease pathogenesis.

引用

页码：1978 / 1991

页数：14

共 69 条

[41] High-affinity binding to the GM-CSF receptor requires intact N-glycosylation sites in the extracellular domain of the β subunit [J].