Journal
GENE THERAPY
Volume 21, Issue 3, Pages 298-308Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gt.2013.85
Keywords
animal model; brain; electron microscopy; leptin; cell culture
Categories
Funding
- Instituto de Salud Carlos III [PI06/0155, F152009/01636]
- Fundacion Investigacion Medial Mutua Madrileria [2008/93, 2010/0004]
- CIBERNED [BESAD-P.2010]
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There is growing evidence that leptin is able to ameliorate Alzheimer's disease (AD)-like pathologies, including brain amyloid-beta (A beta) 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 A beta 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 A beta(42)-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 A beta-targeted treatment of mouse model of AD.
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