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Increases in hypertension-induced cerebral microhemorrhages exacerbate gait dysfunction in a mouse model of Alzheimer’s disease

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Abstract

Clinical studies show that cerebral amyloid angiopathy (CAA) associated with Alzheimer’s disease (AD) and arterial hypertension are independent risk factors for cerebral microhemorrhages (CMHs). To test the hypothesis that amyloid pathology and hypertension interact to promote the development of CMHs, we induced hypertension in the Tg2576 mouse model of AD and respective controls by treatment with angiotensin II (Ang II) and the NO synthesis inhibitor L-NAME. The number, size, localization, and neurological consequences (gait alterations) of CMHs were compared. We found that compared to control mice, in TG2576 mice, the same level of hypertension led to significantly increased CMH burden and exacerbation of CMH-related gait alterations. In hypertensive TG2576 mice, CMHs were predominantly located in the cerebral cortex at the cortical-subcortical boundary, mimicking the clinical picture seen in patients with CAA. Collectively, amyloid pathologies exacerbate the effects of hypertension, promoting the genesis of CMHs, which likely contribute to their deleterious effects on cognitive function. Therapeutic strategies for prevention of CMHs that reduce blood pressure and preserve microvascular integrity are expected to exert neuroprotective effects in high-risk elderly AD patients.

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Funding

This work was 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 National Institute of General Medical Sciences Oklahoma Shared Clinical and Translational Resources (OSCTR) (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). The funding sources had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

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Author notes

  1. Ádám Nyúl-Tóth, Stefano Tarantini and Andriy Yabluchanskiy contributed equally to this work.

Authors and Affiliations

  1. Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Ádám Nyúl-Tóth, Stefano Tarantini, Tamas Kiss, Peter Toth, Amber Tarantini, Andriy Yabluchanskiy, Anna Csiszar & Zoltan Ungvari

  2. International Training Program in Geroscience, Institute of Biophysics, Biological Research Centre, Szeged, Hungary

    Ádám Nyúl-Tóth

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

    Stefano Tarantini, Peter Toth, Amber Tarantini & Zoltan Ungvari

  4. International Training Program in Geroscience, Theoretical Medicine Doctoral School/Departments of Medical Physics and Informatics & Cell Biology and Molecular Medicine, University of Szeged, Szeged, Hungary

    Tamas Kiss, Anna Csiszar & Zoltan Ungvari

  5. International Training Program in Geroscience, Doctoral School of Clinical Medicine, Department of Neurosurgery and Szentagothai Research Center, Medical School, University of Pecs, Pecs, Hungary

    Peter Toth

  6. Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Veronica Galvan

  7. Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Veronica Galvan

  8. South Texas Veterans Health Care System, San Antonio, TX, USA

    Veronica Galvan

  9. Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Veronica Galvan

  10. Department of Biochemistry and Molecular Biology, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA

    Zoltan Ungvari

Authors
  1. Ádám Nyúl-Tóth
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  2. Stefano Tarantini
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  3. Tamas Kiss
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  4. Peter Toth
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  5. Veronica Galvan
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  6. Amber Tarantini
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  7. Andriy Yabluchanskiy
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  8. Anna Csiszar
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  9. Zoltan Ungvari
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Corresponding author

Correspondence to Zoltan Ungvari.

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Nyúl-Tóth, Á., Tarantini, S., Kiss, T. et al. Increases in hypertension-induced cerebral microhemorrhages exacerbate gait dysfunction in a mouse model of Alzheimer’s disease. GeroScience 42, 1685–1698 (2020). https://doi.org/10.1007/s11357-020-00256-3

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  • DOI: https://doi.org/10.1007/s11357-020-00256-3

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