title: Aβ₁₋₄₂-RAGE interaction disrupts tight junctions of the blood-brain barrier via Ca²⁺-calcineurin signaling.
abstract: The blood-brain barrier (BBB), which is formed by adherens and tight junctions (TJs) of endothelial cells, maintains homeostasis of the brain. Disrupted intracellular Ca²⁺ homeostasis and breakdown of the BBB have been implicated in the pathogenesis of Alzheimer's disease (AD). The receptor for advanced glycation end products (RAGE) is known to interact with amyloid β-peptide (Aβ) and mediate Aβ transport across the BBB, contributing to the deposition of Aβ in the brain. However, molecular mechanisms underlying Aβ-RAGE interaction-induced alterations in the BBB have not been identified. We found that Aβ₁₋₄₂ induces enhanced permeability, disruption of zonula occludin-1 (ZO-1) expression in the plasma membrane, and increased intracellular calcium and matrix metalloproteinase (MMP) secretion in cultured endothelial cells. Neutralizing antibodies against RAGE and inhibitors of calcineurin and MMPs prevented Aβ₁₋₄₂-induced changes in ZO-1, suggesting that Aβ-RAGE interactions alter TJ proteins through the Ca²⁺-calcineurin pathway. Consistent with these in vitro findings, we found disrupted microvessels near Aβ plaque-deposited areas, elevated RAGE expression, and enhanced MMP secretion in microvessels of the brains of 5XFAD mice, an animal model for AD. We have identified a potential molecular pathway underlying Aβ-RAGE interaction-induced breakage of BBB integrity. This pathway might play an important role in the pathogenesis of AD.
authors: Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, Seoul 110-799, Korea.
authors: Sun-Young
authors: SY
authors: Kook
authors: Hyun Seok
authors: HS
authors: Hong
authors: Minho
authors: M
authors: Moon
authors: Chang Man
authors: CM
authors: Ha
authors: Sunghoe
authors: S
authors: Chang
authors: Inhee
authors: I
authors: Mook-Jung
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology*; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002461:Cell Line, Transformed; D057167:Claudins / Q000378:metabolism; D003911:Dextrans / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D021621:Imaging, Three-Dimensional; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D011480:Protease Inhibitors / Q000494:pharmacology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016559:Tacrolimus / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D014162:Transfection; D062826:Zonula Occludens-1 Protein
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D057167:Claudins; D003911:Dextrans; D004151:Dipeptides; D051272:Glucose Transporter Type 1; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D010750:Phosphoproteins; D053764:Presenilin-1; D011480:Protease Inhibitors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C495678:Slc2a1 protein, mouse; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; C075222:amyloid beta-protein (1-42); C015219:fluorescein isothiocyanate dextran; D019703:Calcineurin; D020782:Matrix Metalloproteinases; D016650:Fluorescein-5-isothiocyanate; D002118:Calcium; D016559:Tacrolimus