Journal
ANTIOXIDANTS & REDOX SIGNALING
Volume 15, Issue 5, Pages 1167-1178Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2011.3895
Keywords
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Funding
- 'Internationale Stichting Alzheimer Onderzoek' (ISAO) [07517, 09506]
- European Commission [LSHB-CT-2005-511977]
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Cerebral amyloid angiopathy (CAA) is frequently observed in Alzheimer's disease (AD) and is characterized by deposition of amyloid beta (A beta) in leptomeningeal and cortical brain vasculature. In 40% of AD cases, A beta 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 A beta-laden capillaries surrounded by NADPH oxidase-2 (NOX-2)-positive activated microglia. Importantly, we observed abundant vascular expression of the A beta transporter receptor for advanced glycation endproducts (RAGE). To unravel the underlying mechanism, a human brain endothelial cell line was stimulated with A beta 1-42 to analyze the effects of A beta. 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 A beta 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. Antioxid. Redox Signal. 15, 1167-1178.
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