Journal Article

Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

Han, Byung Hee, Nelson, James W., Yoo, Min, Basak, Jacob, Singh, Itender, Holtzman, David M., Johnson, Andrew W., Milner, Eric, Zhou, Meng-liang, Vellimana, Ananth K., Cirrito, John R., Dietrich, Hans H., Zipfel, Gregory Joseph, Liao, Fan

2015

Overview

Significance One of the hallmarks of Alzheimer’s disease (AD) is cerebral amyloid angiopathy (CAA), which is a strong and independent risk factor for cerebral hemorrhage, ischemic stroke, and dementia. However, the mechanisms by which CAA contributes to these conditions are poorly understood. Results from the present study provide strong evidence that vascular oxidative stress plays a causal role in CAA-induced cerebrovascular dysfunction, CAA-induced cerebral hemorrhage, and CAA formation, itself. They also suggest that NADPH oxidase is the source of this oxidative stress and that strategies to inhibit NADPH oxidase may have therapeutic potential in patients with AD and CAA. Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid β peptide (Aβ) within walls of cerebral arteries and is an important cause of intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in elderly patients with and without Alzheimer’s Disease (AD). NADPH oxidase-derived oxidative stress plays a key role in soluble Aβ-induced vessel dysfunction, but the mechanisms by which insoluble Aβ in the form of CAA causes cerebrovascular (CV) dysfunction are not clear. Here, we demonstrate evidence that reactive oxygen species (ROS) and, in particular, NADPH oxidase-derived ROS are a key mediator of CAA-induced CV deficits. First, the NADPH oxidase inhibitor, apocynin, and the nonspecific ROS scavenger, tempol, are shown to reduce oxidative stress and improve CV reactivity in aged Tg2576 mice. Second, the observed improvement in CV function is attributed both to a reduction in CAA formation and a decrease in CAA-induced vasomotor impairment. Third, anti-ROS therapy attenuates CAA-related microhemorrhage. A potential mechanism by which ROS contribute to CAA pathogenesis is also identified because apocynin substantially reduces expression levels of ApoE—a factor known to promote CAA formation. In total, these data indicate that ROS are a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage. Thus, ROS and, in particular, NADPH oxidase-derived ROS are a promising therapeutic target for patients with CAA and AD.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Acetophenones - pharmacology / Aging / Aging - pathology / Alzheimer disease / Alzheimer's disease / amyloid / Animals / Apolipoproteins E - metabolism / Astrocytes - drug effects / Astrocytes - metabolism / Astrocytes - pathology / Biological Sciences / Brain / Brain - drug effects / Brain - pathology / Brain - physiopathology / Cerebral Amyloid Angiopathy - complications / Cerebral Amyloid Angiopathy - pathology / Cerebral Amyloid Angiopathy - physiopathology / Cerebral Arteries - pathology / Cerebral Arteries - physiopathology / Cerebral Hemorrhage - complications / Cerebral Hemorrhage - pathology / Cerebral Hemorrhage - physiopathology / Cricetinae / Cyclic N-Oxides - pharmacology / Hemorrhage / Humans / mice / Mice, Inbred C57BL / Mice, Transgenic / Microglia - drug effects / Microglia - metabolism / Microglia - pathology / Muscle, Smooth, Vascular - pathology / Myocytes, Smooth Muscle - drug effects / Myocytes, Smooth Muscle - metabolism / Myocytes, Smooth Muscle - pathology / NAD(P)H oxidase (H2O2-forming) / NADP (coenzyme) / Oxidative stress / Oxidative Stress - drug effects / Oxygen / Pathogenesis / patients / PNAS Plus / reactive oxygen species / Reactive Oxygen Species - metabolism / risk factors / Rodents / Spin Labels / stroke / Vasomotor System - drug effects / Vasomotor System - pathology / Vasomotor System - physiopathology