title: Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice.
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.
authors: Departments of Neurological Surgery, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110.
authors: Byung Hee
authors: BH
authors: Han
authors: Departments of Neurological Surgery.
authors: Meng-Liang
authors: ML
authors: Zhou
authors: Departments of Neurological Surgery.
authors: Andrew W
authors: AW
authors: Johnson
authors: Departments of Neurological Surgery, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110.
authors: Itender
authors: I
authors: Singh
authors: Neurology, and.
authors: Fan
authors: F
authors: Liao
authors: Departments of Neurological Surgery.
authors: Ananth K
authors: AK
authors: Vellimana
authors: Departments of Neurological Surgery.
authors: James W
authors: JW
authors: Nelson
authors: Departments of Neurological Surgery.
authors: Eric
authors: E
authors: Milner
authors: Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110 Neurology, and.
authors: John R
authors: JR
authors: Cirrito
authors: Neurology, and.
authors: Jacob
authors: J
authors: Basak
authors: Departments of Neurological Surgery.
authors: Min
authors: M
authors: Yoo
authors: Departments of Neurological Surgery, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110.
authors: Hans H
authors: HH
authors: Dietrich
authors: Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110 Neurology, and Developmental Biology, and.
authors: David M
authors: DM
authors: Holtzman
authors: Departments of Neurological Surgery, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110 Neurology, and zipfelg@wustl.edu.
authors: Gregory Joseph
authors: GJ
authors: Zipfel
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000375:Aging / Q000473:pathology*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016657:Cerebral Amyloid Angiopathy / Q000150:complications / Q000473:pathology* / Q000503:physiopathology*; D002536:Cerebral Arteries / Q000473:pathology / Q000503:physiopathology; D002543:Cerebral Hemorrhage / Q000150:complications / Q000473:pathology* / Q000503:physiopathology*; D006224:Cricetinae; D003497:Cyclic N-Oxides / Q000494:pharmacology; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013113:Spin Labels; D014666:Vasomotor System / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*
chemical_list: D000098:Acetophenones; D001057:Apolipoproteins E; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; C056165:acetovanillone; C001803:tempol
keywords: Alzheimer's disease; NADPH oxidase; cerebral amyloid angiopathy; reactive oxygen species; vasomotor dysfunction