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Proc Natl Acad Sci U S A. 2015 Feb 24;112(8):E881-90. doi: 10.1073/pnas.1414930112. Epub 2015 Feb 9.

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

Author information

1
Departments of Neurological Surgery, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110.
2
Departments of Neurological Surgery.
3
Neurology, and.
4
Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110 Neurology, and.
5
Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110 Neurology, and Developmental Biology, and.
6
Departments of Neurological Surgery, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110 Neurology, and zipfelg@wustl.edu.

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.

KEYWORDS:

Alzheimer's disease; NADPH oxidase; cerebral amyloid angiopathy; reactive oxygen species; vasomotor dysfunction

PMID:
25675483
PMCID:
PMC4345564
DOI:
10.1073/pnas.1414930112
[Indexed for MEDLINE]
Free PMC Article

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