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Alleviation of Aβ-induced cognitive impairment by ultrasound-mediated gene transfer of HGF in a mouse model

Gene Therapy volume 15, pages 561–571 (2008)Cite this article

Abstract

A new therapeutic approach to treat Alzheimer's disease (AD) is needed, and the use of growth factors is considered to be a candidate. Hepatocyte growth factor (HGF) is a unique multifunctional growth factor, which has the potential effect to exert neurotrophic action and induce angiogenesis. In this study, we examined the effects of overexpression of human HGF plasmid DNA using ultrasound-mediated gene transfer into the brain in an Aβ-infused cognitive dysfunction mouse model. We demonstrated that HGF gene transfer significantly alleviated Aβ-induced cognitive impairment in mice in behavioral tests. These beneficial effects of HGF might be due to (1) significant recovery of the vessel density in the dentate gyrus of the hippocampus, (2) upregulation of BDNF, (3) a significant decrease in oxidative stress and (4) synaptic enhancement. A pharmacological approach including gene therapy to increase the HGF level in combination with anti-Aβ therapy might be a new therapeutic option for the treatment of AD.

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Acknowledgements

This work was supported in part by a grant-in-aid for scientific research from the Organization for Pharmaceutical Safety and Research, a grant-in-aid from National Institute of Biomedical Innovation (to RM), The Ministry of Public Health and Welfare (to RM) and Takeda Science Foundation (to RM), and grants-in-aid from Japan Promotion of Science, the Japanese Ministry of Education, Culture, Sports, Science and Technology (to RM, NS), Novartis, Chiyoda and the Kanae Foundation (to NS). We thank Dr Hisae Sumi (Department of Neurology, Osaka University Graduate School of Medicine) for critical advice on immunostaining, and also thank Dr Yoshiaki Taniyama for critical advice on ultrasound-mediated gene transfer. We thank Drs Hironori Nakagami, Junya Azuma and Kaori Nagao for helpful discussion, and Ms Hizuki Hamada for technical assistance.

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Authors and Affiliations

  1. Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Yamadaoka, Suita, Japan

    D Takeuchi, N Sato, H Kurinami, S Takeda, M Shinohara & R Morishita

  2. Department of Geriatric Medicine, Graduate School of Medicine, Osaka University, Yamadaoka, Suita, Japan

    D Takeuchi, N Sato, H Kurinami, S Takeda, M Shinohara & T Ogihara

  3. Department of Advanced Clinical Science and Therapeutics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    M Shimamura

  4. Research Institute for Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Ikeda, Osaka, Japan

    S Suzuki & M Kojima

  5. Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan

    S Suzuki & M Kojima

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  1. D Takeuchi
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Correspondence to R Morishita.

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Takeuchi, D., Sato, N., Shimamura, M. et al. Alleviation of Aβ-induced cognitive impairment by ultrasound-mediated gene transfer of HGF in a mouse model. Gene Ther 15, 561–571 (2008). https://doi.org/10.1038/sj.gt.3303094

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