Neuroinflammation and Blood-Brain Barrier Changes in Capillary Amyloid Angiopathy

Introduction: β-Amyloid (Aβ) accumulation in cortical capillaries is a variant of cerebral amyloid angiopathy (CAA) referred to as capillary CAA (capCAA). capCAA is associated with a neuroinflammatory response. In vitro studies indicate that Aβ induces reactive oxygen species (ROS) production, mainly generated through NADPH oxidase (NOX), by activated microglia. ROS in turn can induce altered expression of tight junctions (TJ), which are essential for blood-brain barrier (BBB) function. Whether the function of the BBB is affected in the brains of Alzheimer's disease (AD) patients with comorbid capCAA remains elusive. Cases with capCAA and no other AD-related changes allow studying capCAA-associated BBB alterations independent of AD pathology. Aim: In this study, we have investigated BBB alterations in capCAA and addressed the role of the neuroinflammatory response. Methods: Human postmortem brain tissue with capCAA was analyzed by immunohistochemical staining. Results: In this study, we show for the first time a dramatic loss of TJ proteins claudin-5, occludin and ZO-1 in Aβ-laden capillaries. In addition, affected capillaries are associated with clusters of NOX-2-positive activated microglia. Disrupted BBB function was observed by increased presence of fibrinogen around the affected capillaries. Conclusions: Our data provide support for the early observation that neuroinflammatory response is involved in the altered expression of TJs in endothelial cells and loss of BBB integrity in capCAA. Copyright © 2012 S. Karger AG, Basel

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

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. © 2011 Mary Ann Liebert, Inc