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N-Acetyl Transferase, Shati/Nat8l, in the Dorsal Hippocampus Suppresses Aging-induced Impairment of Cognitive Function in Mice

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Abstract

As the elderly population rapidly increases worldwide, the onset of cognitive dysfunction is expected to increase. Although neuronal plasticity, neurogenesis, and mitochondrial dysfunction have been reported to be involved in cognitive function, the detailed mechanism of cognitive impairment accompanied by aging is poorly understood as there are many confounding factors associated with aging. Therefore, effective treatments for aging have not yet been developed, and the establishment of therapeutic strategies has not progressed accordingly. We have previously found a decline of cognitive function in the developmental stage in mice who lack the expression of Shati/Nat8l, an N-acetyl transferase However, the contribution of Shati/Nat8l to cognitive impairment in aged mice has not yet been investigated. In this study, we aimed to investigate the role of Shati/Nat8l in cognitive function during aging. We observed a reduction in Shati/Nat8l mRNA expression in the dorsal hippocampus of mice as a result of their aging. Moreover, the cognitive dysfunction observed in aged mice was reversed by Shati/Nat8l overexpression in the dorsal hippocampus. Shati/Nat8l overexpression in the dorsal hippocampus of mice did not alter the expression of neurotrophic factors or mitochondrial function-related genes, including Bdnf or Pgc-1α, which are suggested to be downstream genes of Shati/Nat8l. Decreased N-acetyl aspartate (NAA) in aged mice was upregulated by Shati/Nat8l overexpression, suggesting that the Shati/Nat8l-NAA pathway determines cognitive function with aging. Taken together, Shati/Nat8l and NAA in the dorsal hippocampus may be novel targets for the treatment of cognitive impairment.

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Data Availability

The datasets generated and/or analyzed during the current study are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank Naomi Takino and Mika Ito for technical assistance in producing the Shati/Nat8l vectors.

Funding

This research was supported by a Grant-in-Aid for Scientific Research (KAKENHI) (B) [JSPS KAKENHI Grant Number, 26293213, JP21H02632] (SM, AN), Kobayashi Foundation (AN), AdAMS (Ac210045, AN) and Smoking Research Foundation Grant for Biomedical Research and Foundation (AN). HM was supported by a Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan. The funders played no role in the study design, data collection or analysis, decision to publish, or manuscript preparation.

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Authors and Affiliations

  1. Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

    Hajime Miyanishi, Ayumu Kitazawa, Naotaka Izuo & Atsumi Nitta

  2. Division of Neurological Gene Therapy, Center for Open Innovation, Jichi Medical University, Shimotsuke, Japan

    Shin-ichi Muramatsu

  3. Center for Gene & Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Shin-ichi Muramatsu

Authors
  1. Hajime Miyanishi
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  2. Ayumu Kitazawa
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  3. Naotaka Izuo
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  4. Shin-ichi Muramatsu
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  5. Atsumi Nitta
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Contributions

Hajime Miyanishi, Ayumu Kitazawa and Atsumi Nitta conceived and designed the study. Material preparation, data collection, and analysis were performed by Hajime Miyanishi, Ayumu Kitazawa, Naotaka Izuo, and Atsumi Nitta. AAV vectors were provided by Shin-ichi Muramatsu. The first draft of the manuscript was written by Hajime Miyanishi and it was confirmed by Atsumi Nitta. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Atsumi Nitta.

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Conflict of Interest

SM has equity in Gene Therapy Research Institution, Co., Ltd., which commercializes the use of AAV vectors for gene therapy applications. To the extent that the work in this manuscript increases the value of these commercial holdings, SM has conflicts of interest. The other authors have no relevant financial or nonfinancial interests to disclose.

Ethical Approval

All experimental procedures followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and they were approved by the Committee for Animal Experiments at the University of Toyama (2021PHA-16, 20).

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Miyanishi, H., Kitazawa, A., Izuo, N. et al. N-Acetyl Transferase, Shati/Nat8l, in the Dorsal Hippocampus Suppresses Aging-induced Impairment of Cognitive Function in Mice. Neurochem Res 47, 2703–2714 (2022). https://doi.org/10.1007/s11064-022-03594-0

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  • DOI: https://doi.org/10.1007/s11064-022-03594-0

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