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

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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.

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Funding

This work was financially supported by grants from the American Heart Association (ST), the Oklahoma Center for the Advancement of Science and Technology (to AC, AY, ZU), the National Institute on Aging (R01-AG047879; R01-AG038747; R01-AG055395), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218 to AC, R01-NS100782 to ZU), the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (GM104938, to AY), the Presbyterian Health Foundation (to ZU, AC, AY), the NIA-supported Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), and the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337).

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Authors and Affiliations

  1. Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience, Department of Biochemistry, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA

    Anna Csiszar, Andriy Yabluchanskiy, Anna Ungvari, Zoltan Ungvari & Stefano Tarantini

  2. International Training Program in Geroscience, Theoretical Medicine Doctoral School, Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary

    Anna Csiszar & Stefano Tarantini

  3. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary

    Anna Csiszar & Zoltan Ungvari

  4. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Semmelweis University, Budapest, Hungary

    Zoltan Ungvari & Stefano Tarantini

  5. Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Zoltan Ungvari

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  1. Anna Csiszar
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  2. Andriy Yabluchanskiy
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  3. Anna Ungvari
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  4. Zoltan Ungvari
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  5. Stefano Tarantini
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Correspondence to Stefano Tarantini.

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Csiszar, A., Yabluchanskiy, A., Ungvari, A. et al. Overexpression of catalase targeted to mitochondria improves neurovascular coupling responses in aged mice. GeroScience 41, 609–617 (2019). https://doi.org/10.1007/s11357-019-00111-0

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