title: Intracerebral GM-CSF contributes to transendothelial monocyte migration in APP/PS1 Alzheimer's disease mice.
abstract: 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.
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, P.R. China.
authors.forename: De S
authors.initials: S
authors.lastname: Shang
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, P.R. China.
authors.forename: Yi M
authors.initials: YM
authors.lastname: Yang
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, P.R. China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Tian
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, P.R. China.
authors.forename: Jiu S
authors.initials: JS
authors.lastname: Jiang
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, P.R. China.
authors.forename: Yan B
authors.initials: YB
authors.lastname: Dong
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, P.R. China.
authors.forename: Wei D
authors.initials: WD
authors.lastname: Zhao
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, P.R. China.
authors.forename: Wen G
authors.initials: WG
authors.lastname: Fang
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, P.R. China yhchen@mail.cmu.edu.cn.
authors.forename: Yu H
authors.initials: YH
authors.lastname: Chen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D053764:Presenilin-1 / Q000235:genetics; D017208:Rats, Wistar; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D053764:Presenilin-1; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Alzheimer’s disease; CSF2RB; granulocyte-macrophage colony-stimulating factor; monocyte infiltration