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Angiotensin receptor blocker use is associated with upregulation of the memory-protective angiotensin type 4 receptor (AT4R) in the postmortem brains of individuals without cognitive impairment

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Abstract

The reported primary dementia-protective benefits of angiotensin II type 1 receptor (AT1R) blockers (ARB) are believed, at least in part, to arise from systemic effects on blood pressure. However, there is a specific and independently regulated brain renin-angiotensin system (RAS). Brain RAS acts mainly through three receptor subtypes; AT1R, AT2R, and AT4R. The AT1R promotes inflammation and mitochondrial reactive oxygen species generation. AT2R increases nitric oxide. AT4R is essential for dopamine and acetylcholine release. It is unknown whether ARB use is associated with changes in the brain RAS. Here, we compared the impact of treatment with ARB on not cognitively impaired individuals and individuals with Alzheimer’s dementia using postmortem frontal-cortex samples of age- and sex-matched participants (70–90 years old, n = 30 in each group). We show that ARB use is associated with higher brain AT4R, lower oxidative stress, and amyloid-β burden in NCI participants. In AD, ARB use was associated with lower brain AT1R but had no impact on inflammation, oxidative stress, or amyloid-β burden. Our results may suggest a potential role for AT4R in the salutary effects for ARB on the brains of not cognitively impaired older adults.

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Acknowledgements

Figure 7 was created with BioRender.com.

Funding

This work was supported by the Bright Focus Foundation Research Award (PMA), the Johns Hopkins University Claude D. Pepper Older Americans Independence Center, which is funded by the National Institute on Aging of the National Institutes of Health under award number P30AG021334 and NIH Grants R01AG046441 and K23 AG035005, and R01AG17917; and the Nathan W. and Margaret T. Shock Aging Research Foundation, Nathan Shock Scholar in Aging (PMA). This research was supported in part by the Intramural Research Program at the National Institute on Aging. Its contents are solely the authors’ responsibility and do not necessarily represent the official view of the NIH.

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Authors and Affiliations

  1. Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, 21224, USA

    Caglar Cosarderelioglu, Lolita S. Nidadavolu, Ruth Marx-Rattner, Laura Powell, Qian-Li Xue, Esther S. Oh, Jeremy D. Walston & Peter M. Abadir

  2. Department of Internal Medicine, Division of Geriatrics, Ankara University School of Medicine, Ankara, Turkey

    Caglar Cosarderelioglu

  3. Department of Medical Biology, Hacettepe University School of Medicine, Ankara, Turkey

    Caglar Cosarderelioglu & Pervin Dincer

  4. Department of Medicine, Division of Geriatrics, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA

    Claudene J. George

  5. Johns Hopkins University Center On Aging and Health, Baltimore, MD, USA

    Qian-Li Xue

  6. Department of Biostatistics, Bloomberg School of Public Health, Baltimore, MD, USA

    Jing Tian

  7. National Institute On Aging, National Institutes of Health, Baltimore, MD, USA

    Luigi Ferrucci

  8. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA

    David A. Bennett

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  1. Caglar Cosarderelioglu
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Cosarderelioglu, C., Nidadavolu, L.S., George, C.J. et al. Angiotensin receptor blocker use is associated with upregulation of the memory-protective angiotensin type 4 receptor (AT4R) in the postmortem brains of individuals without cognitive impairment. GeroScience 45, 371–384 (2023). https://doi.org/10.1007/s11357-022-00639-8

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