title: Amyloid Beta induces oxidative stress-mediated blood-brain barrier changes in capillary amyloid angiopathy.
abstract: Cerebral amyloid angiopathy (CAA) is frequently observed in Alzheimer's disease (AD) and is characterized by deposition of amyloid beta (Aβ) in leptomeningeal and cortical brain vasculature. In 40% of AD cases, Aβ mainly accumulates in cortical capillaries, a phenomenon referred to as capillary CAA (capCAA). The aim of this study was to investigate blood-brain barrier (BBB) alterations in CAA-affected capillaries with the emphasis on tight junction (TJ) changes. First, capCAA brain tissue was analyzed for the distribution of TJs. Here, we show for the first time a dramatic loss of occludin, claudin-5, and ZO-1 in Aβ-laden capillaries surrounded by NADPH oxidase-2 (NOX-2)-positive activated microglia. Importantly, we observed abundant vascular expression of the Aβ transporter receptor for advanced glycation endproducts (RAGE). To unravel the underlying mechanism, a human brain endothelial cell line was stimulated with Aβ1-42 to analyze the effects of Aβ. We observed a dose-dependent cytotoxicity and increased ROS generation, which interestingly was reversed by administration of exogenous antioxidants, NOX-2 inhibitors, and by blocking RAGE. Taken together, our data evidently show that Aβ is toxic to brain endothelial cells via binding to RAGE and induction of ROS production, which ultimately leads to disruption of TJs and loss of BBB integrity.
authors.affiliation: Department of Molecular Cell Biology and Immunology (MCBI), VU University Medical Center, Amsterdam, The Netherlands. a.carrano@vumc.nl
authors.forename: Anna
authors.initials: A
authors.lastname: Carrano
authors.forename: Jeroen J M
authors.initials: JJ
authors.lastname: Hoozemans
authors.forename: Saskia M
authors.initials: SM
authors.lastname: van der Vies
authors.forename: Annemieke J M
authors.initials: AJ
authors.lastname: Rozemuller
authors.forename: Jack
authors.initials: J
authors.lastname: van Horssen
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D017628:Microglia / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D062793:Occludin; D018384:Oxidative Stress / Q000187:drug effects; D010750:Phosphoproteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism / Q000473:pathology; D062826:Zonula Occludens-1 Protein
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D010750:Phosphoproteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases