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

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

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)E881-E890
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number8
DOIs
StatePublished - Feb 24 2015

Keywords

  • Alzheimer' s disease
  • Cerebral amyloid angiopathy
  • NADPH oxidase
  • Reactive oxygen species
  • Vasomotor dysfunction

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