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.
Subject(s)
Alzheimer Disease/blood , Blood-Brain Barrier/drug effects , Capillary Permeability/drug effects , Cell Movement/drug effects , Endothelium, Vascular/drug effects , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Monocytes/cytology , Aged , Aged, 80 and over , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Animals , Blood-Brain Barrier/metabolism , Disease Models, Animal , Endothelium, Vascular/metabolism , Female , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , HEK293 Cells , Humans , Male , Mice, Transgenic , Middle Aged , Monocytes/metabolism , Monocytes/physiology , Presenilin-1/genetics , Rats, Wistar , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolismABSTRACT
Comprehensive and structured annotations for all genes on a microarray chip are essential for the interpretation of its expression data. Currently, most chip gene annotations are one-line free text descriptions that are often partial, outdated and unsuitable for large-scale data analysis. Therefore the interpretation of microarray gene expression clusters is often limited. Although researchers can manually navigate a collection of databases for better annotations, it is only practical for limited number of genes. Existing meta-databases fail to provide comprehensive categorized annotations for hundreds of genes simultaneously. We have developed an automatic system to address this issue. GeneView system monitors various data sources, extracts gene information from a source whenever it is updated, comprehensively matches genes, and integrates them into a central database by categories, such as pathway, genetic mapping, phenotype, expression profile, domain structure, protein interaction, disease association, and references. The system consists of four major components: (1) relational database; (2) data processing; (3) user curation; (4) data query. We evaluated it by analyzing genes on cDNA and Affymetrix Oligo chips. In both cases, the system provided more accurate and comprehensive information than those provided by the vendors or the chip users, and helped identify new common functions among genes in the same expression clusters.
