Alleviation of A|[beta]|-induced cognitive impairment by ultrasound-mediated gene transfer of HGF in a mouse model

doi:doi:10.1038/sj.gt.3303094

Gene Therapy (2008) 15, 561–571; doi:10.1038/sj.gt.3303094; published online 21 February 2008

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

D Takeuchi^1,2, N Sato^1,2, M Shimamura³, H Kurinami^1,2, S Takeda^1,2, M Shinohara^1,2, S Suzuki^4,5, M Kojima^4,5, T Ogihara² and R Morishita¹

¹Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Yamadaoka, Suita, Japan
²Department of Geriatric Medicine, Graduate School of Medicine, Osaka University, Yamadaoka, Suita, Japan
³Department of Advanced Clinical Science and Therapeutics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
⁴Research Institute for Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Ikeda, Osaka, Japan
⁵Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan

Correspondence: Dr Professor R Morishita, Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: morishit@cgt.med.osaka-u.ac.jp

Received 29 June 2007; Revised 2 December 2007; Accepted 3 December 2007; Published online 21 February 2008.

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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 A beta -infused cognitive dysfunction mouse model. We demonstrated that HGF gene transfer significantly alleviated A beta -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-A beta therapy might be a new therapeutic option for the treatment of AD.