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Leptin gene therapy attenuates neuronal damages evoked by amyloid-β and rescues memory deficits in APP/PS1 mice

Gene Therapy volume 21, pages 298–308 (2014)Cite this article

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Abstract

There is growing evidence that leptin is able to ameliorate Alzheimer’s disease (AD)-like pathologies, including brain amyloid-β (Aβ) burden. In order to improve the therapeutic potential for AD, we generated a lentivirus vector expressing leptin protein in a self-inactivating HIV-1 vector (HIV-leptin), and delivered this by intra-cerebroventricular administration to APP/PS1 transgenic model of AD. Three months after intra-cerebroventricular administration of HIV-leptin, brain Aβ accumulation was reduced. By electron microscopy, we found that APP/PS1 mice exhibited deficits in synaptic density, which were partially rescued by HIV-leptin treatment. Synaptic deficits in APP/PS1 mice correlated with an enhancement of caspase-3 expression, and a reduction in synaptophysin levels in synaptosome preparations. Notably, HIV-leptin therapy reverted these dysfunctions. Moreover, leptin modulated neurite outgrowth in primary neuronal cultures, and rescued them from Aβ42-induced toxicity. All the above changes suggest that leptin may affect multiple aspects of the synaptic status, and correlate with behavioral improvements. Our data suggest that leptin gene delivery has a therapeutic potential for Aβ-targeted treatment of mouse model of AD.

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Acknowledgements

This work was supported by grants from Instituto de Salud Carlos III (PI06/0155, FIS2009/01636), Fundación Investigación Médica Mutua Madrileña (2008/93, 2010/0004) and CIBERNED (BESAD-P.2010). We thank Agnieszka Krzyzanowska, PhD, for the careful revision of this manuscript.

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  1. A M Martín-Moreno

    Present address: 6Present address: MD Anderson Cancer Center, Arturo Soria 270, 28033 Madrid, Spain.,

Authors and Affiliations

  1. Neuroscience Group, Instituto de Investigacion Hospital 12 de Octubre (i+12), Madrid, Spain

    R Pérez-González, D Antequera & E Carro

  2. Center for Networker Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain

    R Pérez-González, D Antequera, A M Martín-Moreno, B Brera, M L de Ceballos & E Carro

  3. Department of Anatomy, Histology and Neuroscience, Universidad Autónoma de Madrid, Madrid, Spain

    M X Alvira-Botero & M Garzón

  4. Universidad Pedagógica y Tecnológica de Colombia, Boyacá, Colombia

    O Robayo

  5. Neurodegeneration Group, Cajal Institute-CSIC, Madrid, Spain

    A M Martín-Moreno, B Brera & M L de Ceballos

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Pérez-González, R., Alvira-Botero, M., Robayo, O. et al. Leptin gene therapy attenuates neuronal damages evoked by amyloid-β and rescues memory deficits in APP/PS1 mice. Gene Ther 21, 298–308 (2014). https://doi.org/10.1038/gt.2013.85

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