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Proinsulin therapy protects against neuroinflammaging and cognitive loss in senescence-accelerated mice

AuthorsSanfeliu, Coral ; Corpas, Rubén ; Hernández-Pinto, Alberto M. ; Porquet, David; Hernández-Sánchez, Catalina ; Bosch, Fátima; Ortega-Aznar, Arantxa; Comellas, Francesc; De la Rosa, Enrique J.
Issue Date16-Oct-2017
CitationIUBMB Focused Meeting (2017)
AbstractChronic low-grade neuroinflammation is tightly associated with brain age-related changes and it is considered a crucial derangement that paves the way to neurodegeneration and dementia. Among other ailments, inflammation may lead to insulin resistance that is a risk factor for Alzheimer’s disease. In this scenario, the hormone precursor proinsulin may have a potential pharmacological use in preventing neuronal death. Proinsulin is a bioactive molecule regulating neural cell death in embryonic processes and it was proven neuroprotective in mouse models of retinal neurodegeneration. We aimed to prove the geroprotective effect of a chronic proinsulin treatment against neuroinflammaging and memory loss in the senescence-accelerated mouse SAMP8. We used a gene therapy procedure through peripheral muscle transduction with an adeno-associated viral vector bearing the human proinsulin gene (AAV-hPi) that yielded sustained release of proinsulin into the bloodstream. One-month old male mice of the SAMP8 strain and the control strain SAMR1 were injected with AAV-hPi or AAV-null vectors. At 6 months of age, proinsulin-treated SAMP8 mice showed totally preserved cognitive capacities both in spatial and recognition paradigms of learning and memory, in contrast to those SAMP8 mice injected with the null vector. Hippocampus analysis showed that proinsulin activated Akt and ATF1/CREB signaling pathways in both SAMR1 and SAMP8 mice. Furthermore, we identified a significant decrease of neuroinflammatory markers in the hippocampus of SAMP8 mice to levels of SAMR1 mice. Strikingly, the marker of astrocyte reactivity GFAP was decreased in both SAMR1 and SAMP8. Furthermore, the connectome network build with all changes induced by proinsulin showed that the decrease of astrocyte reactivity was a central effect in proinsulin neuroprotection. Therefore, the preventive and protective effects of human proinsulin against neuroinflammaging and senescence-related cognitive loss unveil a potential geroprotective therapy to increase healthy brain aging.
DescriptionTrabajo presentado en el IUBMB Focused Meeting on «Molecular aspects of aging and longevity», celebrado en Atenas, del 16 al 19 de octubre de 2017
Appears in Collections:(IIBB) Comunicaciones congresos
(CIB) Comunicaciones congresos
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