title: Leptin gene therapy attenuates neuronal damages evoked by amyloid-β and rescues memory deficits in APP/PS1 mice.
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.
authors.affiliation: 1] Neuroscience Group, Instituto de Investigacion Hospital 12 de Octubre (i+12), Madrid, Spain [2] Center for Networker Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Pérez-González
authors.affiliation: Department of Anatomy, Histology and Neuroscience, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: M X
authors.initials: MX
authors.lastname: Alvira-Botero
authors.affiliation: Universidad Pedagógica y Tecnológica de Colombia, Boyacá, Colombia.
authors.forename: O
authors.initials: O
authors.lastname: Robayo
authors.affiliation: 1] Neuroscience Group, Instituto de Investigacion Hospital 12 de Octubre (i+12), Madrid, Spain [2] Center for Networker Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Antequera
authors.affiliation: Department of Anatomy, Histology and Neuroscience, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Garzón
authors.affiliation: 1] Center for Networker Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain [2] Neurodegeneration Group, Cajal Institute-CSIC, Madrid, Spain.
authors.forename: A M
authors.initials: AM
authors.lastname: Martín-Moreno
authors.affiliation: 1] Center for Networker Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain [2] Neurodegeneration Group, Cajal Institute-CSIC, Madrid, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Brera
authors.affiliation: 1] Center for Networker Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain [2] Neurodegeneration Group, Cajal Institute-CSIC, Madrid, Spain.
authors.forename: M L
authors.initials: ML
authors.lastname: de Ceballos
authors.affiliation: 1] Neuroscience Group, Instituto de Investigacion Hospital 12 de Octubre (i+12), Madrid, Spain [2] Center for Networker Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Carro
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000628:therapy*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism; D007276:Injections, Intraventricular; D020738:Leptin / Q000235:genetics* / Q000378:metabolism; D008569:Memory Disorders / Q000235:genetics / Q000628:therapy*; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics; D013569:Synapses / Q000473:pathology; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D020738:Leptin; D053764:Presenilin-1; D016708:Synaptophysin; C580804:presenilin 1, mouse; D053148:Caspase 3