The effect of age on brain insulin signalling

• Autores: Adrián Martín
• Directores de la Tesis: Carlos G. Dotti (dir. tes.), Félix Hernández Pérez (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2017
• Idioma: español
• Tribunal Calificador de la Tesis: Federico Mayor Menéndez (presid.), Teresa Iglesias Vacas (secret.), Coral Sanfeliu Pujol (voc.), Miguel Medina Padilla (voc.), José Abad Rodríguez (voc.)
• Programa de doctorado: Programa Oficial de Doctorado en Bioquímica, Biología Molecular, Biomedicina y Biotecnología (Biociencias Moleculares)
• Materias:
  • Ciencias de la vida
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • The insulin and IGF-1 signalling pathways are among the most widely studied routes in the organism. Their regulation is of vital importance in processes like metabolic homeostasis or cell development and growth and therefore turned them into the object of exhaustive investigations, aiming at a deep understanding of the different processes they regulate in the different tissues of the organism. However, the intimate mechanisms by which the functions controlled by these peptides are not optimal in certain conditions remain incompletely addressed. In the brain, in addition to a body homeostasis role, a panoply of results indicate that insulin plays a role in cognition, mediated through its capacity to induce a synaptic plasticity event known as long-term depression (LTD). To a lesser extend, IGF-1 has also been related with synaptic transmission and modulation. In addition, the signalling power elicited by these peptides decreases with ageing, thus affecting the different processes they regulate. In this thesis we studied the effect of age on hippocampal insulin signalling. We determined that Insulin-LTD is impaired in the hippocampus of old mice (20-24 month-old) in comparison with adult mice (7-12 month-old). Biochemical data suggest that the functional deficit might be explained by an over-activity of the receptors leading to increased phosphorylation of the cytoplasmic effectors downstream, in turn triggering a negative signalling feedback resulting in pathway desensitisation. Importantly, the hippocampus phenotype is not accompanied by signs of abnormal body insulin sensitivity. Mechanistically, we observed that the mild reduction of cholesterol that normally occurs in the hippocampus of aged mice plays an important role in the desensitisation of the pathway in this brain structure. Restoring hippocampal cholesterol levels in old mice to the values of adult mice allows the restoration of the basal activity of the insulin/IGF-1 signalling and a proper Insulin-LTD. Through FRET imaging and cholesterol loss of function experiments we demonstrate that the cholesterol loss occurring in old neurons leads to ligand-independent activation of the IR and the IGF-1R, consequently driving the posterior desensitising effects observed. The treatment with Voriconazole, an inhibitor of the CYP46A1 enzyme, responsible for the cholesterol loss in old mice hippocampus, effectively avoids the hyper-activation of the IR/IGF-1R signalling and the presence of insulin desensitisation marks on the IR substrate, allowing the return of the pathway to an adult basal state. Altogether these results put age-associated changes in lipid content at a most upstream mechanism of age-associated hippocampal insulin desensitisation.