title: Microglial TNF-α-dependent elevation of MHC class I expression on brain endothelium induced by amyloid-beta promotes T cell transendothelial migration.
abstract: The blood-brain barrier (BBB) normally bars peripheral T lymphocytes from entering the cerebrum. Interestingly, activated T cells exist as infiltrates in the brains of Alzheimer's disease (AD) patients, but little is known about the mechanisms involved. In this study, we observed significantly higher MHC class I expression in rat brain endothelial cells compared with controls following the induction of experimental AD models. An in vitro BBB model, which was constructed with human brain microvascular endothelial cells, was established to study the mechanisms underlying the transendothelial migration of T cells. Using in vitro studies, we demonstrated that secretion of TNF-α from Aβ1-42-treated BV2 microglia contributes to the elevated expression of MHC class I on the brain microvessel endothelium. Transmigration assays and adhesion assays confirmed that the upregulation of MHC class I molecules was associated with T cell transendothelial migration. MHC class I knock-down in HBMECs significantly attenuated the migratory and adhesive capability of the T cells. Interestingly, a TNF-α neutralizing antibody effectively blocked the transendothelial migration of T cells triggered by treatment with the supernatant from Aβ1-42-treated BV2 microglia. We propose that microglia-derived TNF-α upregulates MHC class I molecule expression on brain endothelial cells, which represents a mechanism of T cell migration into the brain. This study may provide a new insight into the potential pathomechanism of Alzheimer's disease.
authors.affiliation: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 92 Bei Er Road, Heping District, Shenyang, 110001, China.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Yang
authors.forename: De-Shu
authors.initials: DS
authors.lastname: Shang
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Zhao
authors.forename: Wen-Gang
authors.initials: WG
authors.lastname: Fang
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Chen
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D008297:Male; D017628:Microglia / Q000276:immunology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013601:T-Lymphocytes / Q000276:immunology*; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42)