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Shati/Nat8l Overexpression Improves Cognitive Decline by Upregulating Neuronal Trophic Factor in Alzheimer’s Disease Model Mice

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Abstract

Alzheimer’s disease (AD) is a type of dementia characterized by the deposition of amyloid β, a causative protein of AD, in the brain. Shati/Nat8l, identified as a psychiatric disease related molecule, is a responsive enzyme of N-acetylaspartate (NAA) synthesis. In the hippocampi of AD patients and model mice, the NAA content and Shati/Nat8l expression were reported to be reduced. Having recently clarified the involvement of Shati/Nat8l in cognitive function, we examined the recovery effect of the hippocampal overexpression of Shati/Nat8l in AD model mice (5XFAD). Shati/Nat8l overexpression suppressed cognitive dysfunction without affecting the Aβ burden or number of NeuN-positive neurons. In addition, brain-derived neurotrophic factor mRNA was upregulated by Shati/Nat8l overexpression in 5XFAD mice. These results suggest that Shati/Nat8l overexpression prevents cognitive dysfunction in 5XFAD mice, indicating that Shati/Nat8l could be a therapeutic target for AD.

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The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

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Acknowledgements

We thank Naomi Takino and Mika Ito (Jichi Medical University, Shimosuke, Japan) for technical assistance in producing the Shati/Nat8l AAV vectors.

Funding

This work was supported by the grant-in-aid for Scientific Research (KAKENHI) (B) [JSPS KAKENHI JP26293213] (to SM) [21H02632] (to AN), [JP22H04922] (to AN) from the Japan Society for the Promotion of Science, Kobayashi Foundation (to AN), and SRF Grant for Biomedical Research and Foundation, Japan (to AN and NI).

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Authors and Affiliations

  1. Department of Pharmaceutical Therapy and Neuropharmacology, School of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Kakeru Chino, Naotaka Izuo, Hiroshi Noike, Kyosuke Uno & Atsumi Nitta

  2. Laboratory of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata-shi, Osaka, Japan

    Kyosuke Uno

  3. Laboratory of Pharmacognosy, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku, Fukuoka, 815-8511, Japan

    Tomoharu Kuboyama

  4. Section of Neuromedical Science, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama, 930-0194, Japan

    Chihiro Tohda

  5. Division of Neurological Gene Therapy, Open Innovation Center, Jichi Medical University, Shimotsuke, 329-0498, Japan

    Shin-Ichi Muramatsu

  6. Center for Gene and Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan

    Shin-Ichi Muramatsu

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  1. Kakeru Chino
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Correspondence to Atsumi Nitta.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical Approval

Animal experiments were performed in accordance with the guidelines of the National Institutes of Health, the Animal Experiment Handling Regulations of the University of Toyama, and the Animal Experiment Regulations of the Ministry of Education, Culture, Sports, Science and Technology. Animal experimental protocols were approved by the Animal Care and Use Committee of the University of Toyama (Approval number A2017INM-1, A2020INM-1) and conducted in accordance with the Institutional Animal Experiment Handling Rules of the University of Toyama. DNA Genetic Recombination Committee of the University of Toyama (G2016PHA-9, G2020PHA-5, G2018INM-1).

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Chino, K., Izuo, N., Noike, H. et al. Shati/Nat8l Overexpression Improves Cognitive Decline by Upregulating Neuronal Trophic Factor in Alzheimer’s Disease Model Mice. Neurochem Res 47, 2805–2814 (2022). https://doi.org/10.1007/s11064-022-03649-2

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