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Brain cellular senescence in mouse models of Alzheimer’s disease

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Abstract

The accumulation of senescent cells contributes to aging pathologies, including neurodegenerative diseases, and its selective removal improves physiological and cognitive function in wild-type mice as well as in Alzheimer’s disease (AD) models. AD models recapitulate some, but not all components of disease and do so at different rates. Whether brain cellular senescence is recapitulated in some or all AD models and whether the emergence of cellular senescence in AD mouse models occurs before or after the expected onset of AD-like cognitive deficits in these models are not yet known. The goal of this study was to identify mouse models of AD and AD-related dementias that develop measurable markers of cellular senescence in brain and thus may be useful to study the role of cellular senescence in these conditions. We measured the levels of cellular senescence markers in the brains of P301S(PS19), P301L, hTau, and 3xTg-AD mice that model amyloidopathy and/or tauopathy in AD and related dementias and in wild-type, age-matched control mice for each strain. Expression of cellular senescence markers in brains of transgenic P301L and 3xTg-AD mice was largely indistinguishable from that in WT control age-matched mice. In contrast, markers of cellular senescence were differentially increased in brains of transgenic hTau and P301S(PS19) mice as compared to WT control mice before the onset of AD-like cognitive deficits. Taken together, our data suggest that P301S(PS19) and hTau mice may be useful models for the study of brain cellular senescence in tauopathies including, but not limited to, AD.

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Funding

These studies were supported by NIH/NIA RF1AG057964-01 to VP and VG; Merit Review Award 5I0 1BX002211-05A1 from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service, 1RF1AG068283-01 the Robert L. Bailey and daughter Lisa K. Bailey Alzheimer’s Fund in memory of Jo Nell Bailey to VG; and a William & Ella Owens Medical Research Foundation Grant, the San Antonio Medical Foundation, and the JMR Barker Foundation to VG, and Diversity Supplement RF1AG057964-01 to RR. These studies were also supported by an award to VG through the NCATS/NIH Clinical and Translational Science Award grant UL1TR002645. AOD was’supported by NIA Training Grant T32AG021890.

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Author notes

  1. These authors Angela O. Dorigatti and Ruben Riordan are contributed equally.

Authors and Affiliations

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

    Angela O. Dorigatti & Veronica Galvan

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

    Angela O. Dorigatti & Veronica Galvan

  3. Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, USA

    Ruben Riordan, Zhen Yu, Grace Ross, Rong Wang & Viviana I. Perez

  4. Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon State University, 351 Linus Pauling Science Center, Corvallis, OR, 97331, USA

    Ruben Riordan, Zhen Yu, Grace Ross, Rong Wang, Nadjalisse Reynolds-Lallement, Kathy Magnusson & Viviana I. Perez

  5. Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, USA

    Nadjalisse Reynolds-Lallement & Kathy Magnusson

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

    Veronica Galvan

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

    Veronica Galvan

  8. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd, BMSB 853, Oklahoma City, OK, 73104, USA

    Veronica Galvan

  9. Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Veronica Galvan

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  1. Angela O. Dorigatti
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  2. Ruben Riordan
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  4. Grace Ross
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  8. Veronica Galvan
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  9. Viviana I. Perez
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Correspondence to Veronica Galvan or Viviana I. Perez.

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Dorigatti, A.O., Riordan, R., Yu, Z. et al. Brain cellular senescence in mouse models of Alzheimer’s disease. GeroScience 44, 1157–1168 (2022). https://doi.org/10.1007/s11357-022-00531-5

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