Overexpression of catalase targeted to mitochondria improves neurovascular coupling responses in aged mice.

Abstract

Moment‐to‐moment adjustment of cerebral blood flow (CBF) to neuronal activity via the homeostatic mechanism known as neurovascular coupling (NVC) has an essential role in maintenance of normal brain function. In advanced age cerebromicrovascular endothelial dysfunction impairs NVC responses, which contribute to age‐related cognitive decline. Recently, we have shown that pharmacological treatments that attenuate mitochondrial production of reactive oxygen species (ROS) provide significant neurovascular protection, improving NVC responses in aged mice. Transgenic mice that overexpress human catalase localized to the mitochondria (mCAT) are protected from age‐related mitochondrial oxidative stress and exhibit a longevity phenotype associated with resistance to several age‐related pathologies. The present study was designed to test the hypothesis that mitochondria‐targeted overexpression of catalase also confers protection against age‐related impairment of NVC responses. To achieve this goal, NVC responses were assessed in aged (24 months old) mCAT mice and compared with those in age‐matched wild‐type mice and young control mice by measuring CBF responses (laser speckle contrast imaging) evoked by contralateral whisker stimulation. We found that mitochondrial overexpression of catalase resulted in improved NVC in aged mice due to preserved NO‐mediated (L‐NAME inhibitable) component of the response. Thus, our present and previous findings demonstrate that interventions that boost mitochondrial antioxidative defenses confer significant cerebromicrovascular protective effects, which preserve NVC responses in aged mice. Our findings provide additional proof‐of‐concept for the potential use of mitochondria‐targeted antioxidants as therapy for prevention of vascular cognitive impairment associated with aging.Support or Funding InformationThis work was supported by grants the Oklahoma Center for the Advancement of Science and Technology, the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (GM104938), the NIA‐supported Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337), and the NIGMS supported Center of Biomedical Research Excellence (CoBRE).