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

Edaravone alleviates Alzheimer’s disease-type pathologies and cognitive deficits

“…In the present study, we found that CAA is substantially reduced, with a reduction in parenchymal Aβ deposition and without an increase in microhemorrhage. ROSs are a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage, implying that the ROS scavenger is an important therapeutic for CAA (42). These findings suggest that Edaravone would also be a promising drug candidate for CAA.…”

Endothelial Dysfunction and Amyloid-β-Induced Neurovascular Alterations

“…Nox subunit is present in 5 isoforms (Nox 1-5) and is a core catalytic subunit of the enzyme (Drummond et al 2011). Nox 1, 2, and 4 isoforms are present in blood vessels of the brain (Han et al 2015; Kazama et al 2004; Miller et al 2005; Park et al 2005; Park et al 2008). Genetic inactivation of Nox2 counteracts the cerebrovascular oxidative stress and the vascular dysfunction induced by Aβ, pointing to NADPH oxidase as the source of the ROS (Park et al 2005; Park et al 2008).…”

Vascular and Metabolic Factors in Alzheimer’s Disease and Related Dementias: Introduction

“…Importantly, these vascular abnormalities are observed in the absence of deposition of Aβ in amyloid plaques or around cerebral blood vessels (cerebral amyloid angiopathy), suggesting that soluble or oligomeric Aβ is the vasotoxic species. The cerebrovascular effects of Aβ are mediated in large part by activation of the free radical-producing enzyme NADPH oxidase through the innate immunity receptor CD36, and are reversible by pharmacological or genetic approaches to scavenge radicals or block their production (Han et al, 2015; Iadecola et al, 1999; Nicolakakis et al, 2008; Park et al, 2013; 2008). However, these neurovascular alterations become irreversible in advanced disease, due to accumulation of Aβ in cerebral blood vessels which leads to damage to endothelium, smooth muscle cells and pericytes (Park et al, 2013; 2014).…”