Proinsulin protects against age-related cognitive loss through anti-inflammatory convergent pathways

Autor: Coral Sanfeliu, David Porquet, Rubén Corpas, Francesc Comellas, Alberto M. Hernández-Pinto, Catalina Hernández-Sánchez, Enrique J. de la Rosa, Arantxa Ortega-Aznar, Fatima Bosch
Přispěvatelé: Universitat Politècnica de Catalunya. Departament de Matemàtiques, Universitat Politècnica de Catalunya. COMBGRAPH - Combinatòria, Teoria de Grafs i Aplicacions, Ministerio de Economía y Competitividad (España), European Commission, Ministerio de Ciencia e Innovación (España)
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Male
Adeno-associated virus (AAV) vectors
0301 basic medicine
Senescence
Aging
medicine.medical_specialty
endocrine system
Neuroimmunomodulation
medicine.medical_treatment
Cognitive loss
Genetic Vectors
Hippocampus
Biology
Injections
Intramuscular
Neuroprotection
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Internal medicine
medicine
Animals
Humans
Cognitive Dysfunction
PI3K/AKT/mTOR pathway
Proinsulin
Pharmacology
Insulin
Neurodegeneration
Enginyeria biomèdica [Àrees temàtiques de la UPC]
Genetic Therapy
Dependovirus
medicine.disease
Inflammaging
Mice
Mutant Strains
Disease Models
Animal
030104 developmental biology
Endocrinology
medicine.anatomical_structure
Adeno-associated virus vector
Astrocytes
Therapy
C-peptide
Proto-Oncogene Proteins c-akt
Biomedicina
030217 neurology & neurosurgery
Astrocyte
Zdroj: UPCommons. Portal del coneixement obert de la UPC
Universitat Politècnica de Catalunya (UPC)
Recercat. Dipósit de la Recerca de Catalunya
instname
Digital.CSIC. Repositorio Institucional del CSIC
Popis: 40 p.-5 fig.
Brain inflammaging is increasingly considered as contributing to age-related cognitive loss and neurodegeneration. Despite intensive research in multiple models, no clinically effective pharmacological treatment has been found yet. Here, in the mouse model of brain senescence SAMP8, we tested the effects of proinsulin, a promising neuroprotective agent that was previously proven to be effective in mouse models of retinal neurodegeneration. Proinsulin is the precursor of the hormone insulin but also upholds developmental physiological effects, particularly as a survival factor for neural cells. Adeno-associated viral vectors of serotype 1 bearing the human proinsulin gene were administered intramuscularly to obtain a sustained release of proinsulin into the blood stream, which was able to reach the target area of the hippocampus. SAMP8 mice and the control strain SAMR1 were treated at 1 month of age. At 6 months, behavioral testing exhibited cognitive loss in SAMP8 mice treated with the null vector. Remarkably, the cognitive performance achieved in spatial and recognition tasks by SAMP8 mice treated with proinsulin was similar to that of SAMR1 mice. In the hippocampus, proinsulin induced the activation of neuroprotective pathways and the downstream signaling cascade, leading to the decrease of neuroinflammatory markers. Furthermore, the decrease of astrocyte reactivity was a central effect, as demonstrated in the connectome network of changes induced by proinsulin. Therefore, the neuroprotective effects of human proinsulin unveil a new pharmacological potential therapy in the fight against cognitive loss in the elderly.
This work was supported by grants: CSD2010-00045 to CS and EJdlR, from the Spanish Ministerio de Economía y Competitividad (MINECO), SAF2016-77703-C2-2-R to CS and MTM2014-60127-P to FC from MINECO and European Regional Development Fund (ERDF), and TRACE (PET08-0282) to FB and EJdlR, from the Spanish Ministerio de Ciencia e Innovación (MICINN).
Databáze: OpenAIRE
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