Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 8, Pages E881-E890Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1414930112
Keywords
Alzheimer's disease; cerebral amyloid angiopathy; reactive oxygen species; NADPH oxidase; vasomotor dysfunction
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Funding
- NIH-National Institute of Neurological Disorders and Stroke [1R01 NS071011-01A1, AG13956]
- Harrington/Zhu Alzheimer Research Fund from the Barnes-Jewish Hospital Foundation
- McDonnell Center for Systems Neuroscience grant
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Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid beta peptide (A beta) 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 A beta-induced vessel dysfunction, but the mechanisms by which insoluble A beta 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.
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