Amyloid Beta induces oxidative stress-mediated blood-brain barrier changes in capillary amyloid angiopathy

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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.

Original languageEnglish
Pages (from-to)1167-78
Number of pages12
JournalAntioxidants and Redox Signaling
Volume15
Issue number5
DOIs
Publication statusPublished - 1 Sep 2011

Cite this

@article{b99d30eb262b4f85b04135f3a9b63027,
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.",
keywords = "Aged, Aged, 80 and over, Amyloid beta-Peptides/toxicity, Antioxidants/pharmacology, Blood-Brain Barrier/metabolism, Capillaries/metabolism, Cell Line, Cerebral Amyloid Angiopathy/genetics, Down-Regulation/drug effects, Endothelial Cells/drug effects, Female, Gene Expression Regulation/drug effects, Humans, Male, Membrane Glycoproteins/metabolism, Membrane Proteins/genetics, Microglia/metabolism, NADPH Oxidase 2, NADPH Oxidases/metabolism, Occludin, Oxidative Stress/drug effects, Phosphoproteins/genetics, RNA, Messenger/genetics, Reactive Oxygen Species/metabolism, Receptor for Advanced Glycation End Products/metabolism, Tight Junctions/metabolism, Zonula Occludens-1 Protein",
author = "Anna Carrano and Hoozemans, {Jeroen J M} and {van der Vies}, {Saskia M} and Rozemuller, {Annemieke J M} and {van Horssen}, Jack and {de Vries}, {Helga E}",
year = "2011",
month = "9",
day = "1",
doi = "10.1089/ars.2011.3895",
language = "English",
volume = "15",
pages = "1167--78",
journal = "Antioxidants and Redox Signaling",
issn = "1523-0864",
publisher = "Mary Ann Liebert Inc.",
number = "5",

}

TY - JOUR

T1 - Amyloid Beta induces oxidative stress-mediated blood-brain barrier changes in capillary amyloid angiopathy

AU - Carrano, Anna

AU - Hoozemans, Jeroen J M

AU - van der Vies, Saskia M

AU - Rozemuller, Annemieke J M

AU - van Horssen, Jack

AU - de Vries, Helga E

PY - 2011/9/1

Y1 - 2011/9/1

N2 - 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.

AB - 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.

KW - Aged

KW - Aged, 80 and over

KW - Amyloid beta-Peptides/toxicity

KW - Antioxidants/pharmacology

KW - Blood-Brain Barrier/metabolism

KW - Capillaries/metabolism

KW - Cell Line

KW - Cerebral Amyloid Angiopathy/genetics

KW - Down-Regulation/drug effects

KW - Endothelial Cells/drug effects

KW - Female

KW - Gene Expression Regulation/drug effects

KW - Humans

KW - Male

KW - Membrane Glycoproteins/metabolism

KW - Membrane Proteins/genetics

KW - Microglia/metabolism

KW - NADPH Oxidase 2

KW - NADPH Oxidases/metabolism

KW - Occludin

KW - Oxidative Stress/drug effects

KW - Phosphoproteins/genetics

KW - RNA, Messenger/genetics

KW - Reactive Oxygen Species/metabolism

KW - Receptor for Advanced Glycation End Products/metabolism

KW - Tight Junctions/metabolism

KW - Zonula Occludens-1 Protein

U2 - 10.1089/ars.2011.3895

DO - 10.1089/ars.2011.3895

M3 - Article

VL - 15

SP - 1167

EP - 1178

JO - Antioxidants and Redox Signaling

JF - Antioxidants and Redox Signaling

SN - 1523-0864

IS - 5

ER -