11 beta-HSD1 Inhibition Rescues SAMP8 Cognitive Impairment Induced by Metabolic Stress
Por:
Puigoriol-Illamola D, Leiva R, Vazquez M, Vázquez S, Griñán-Ferré C and Pallàs M
Publicada:
1 ene 2020
Ahead of Print:
9 ago 2019
Resumen:
Ageing and obesity have been shown to increase the risk of cognitive decline and Alzheimer's disease (AD). Besides, elevated glucocorticoid (GCs) levels cause metabolic stress and have been associated with the neurodegenerative process. Direct pieces of evidence link the reduction of GCs caused by the inhibition of 11 beta-HSD type 1 (11 beta-HSD1) with cognitive improvement. In the present study, we investigated the beneficial effects of 11 beta-HSD1 inhibitor (i) RL-118 after high-fat diet (HFD) treatment in the senescence-accelerated mouse prone 8 (SAMP8). We found an improvement in glucose intolerance induced by HFD in mice treated with RL-118, a significant reduction in 11 beta-HSD1 and glucocorticoid receptor (GR) protein levels. Furthermore, specific modifications in the FGF21 activation after treatment with 11 beta-HSD1i, RL-118, which induced changes in SIRT1/PGC1 alpha/AMPK alpha pathway, were found. Oxidative stress (OS) and reactive oxygen species (ROS), as well as inflammatory markers and microglial activation, were significantly diminished in HFD mice treated with 11 beta-HSD1i. Remarkably, treatment with 11 beta-HSD1i altered PERK pathway in both diet groups, increasing autophagy only in HFD mice group. After RL-118 treatment, a decrease in glycogen synthase kinase 3 (GSK3 beta) activation, Tau hyperphosphorylation, BACE1 protein levels and the product beta-CTF were found. Increases in the non-amyloidogenic secretase ADAM10 protein levels and the product sAPP alpha were found in both treated mice, regardless of the diet. Consequently, beneficial effects on social behaviour and cognitive performance were found in treated mice. Thus, our results support the therapeutic strategy of selective 11 beta-HSD1i for the treatment of age-related cognitive decline and AD.
Filiaciones:
Puigoriol-Illamola D:
Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av Joan XXIII 27-31, 08028, Barcelona, Spain
Institute of Neuroscience, University of Barcelona (NeuroUB), Barcelona, Spain
Leiva R:
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Department de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain
Institute of Biomedicine, University of Barcelona (IBUB), Barcelona, Spain
Vazquez M:
Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av Joan XXIII 27-31, 08028, Barcelona, Spain
Institute of Biomedicine, University of Barcelona (IBUB), Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Vázquez S:
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Department de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain
Institute of Biomedicine, University of Barcelona (IBUB), Barcelona, Spain
Griñán-Ferré C:
Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av Joan XXIII 27-31, 08028, Barcelona, Spain
Institute of Neuroscience, University of Barcelona (NeuroUB), Barcelona, Spain
Pallàs M:
Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av Joan XXIII 27-31, 08028, Barcelona, Spain.
Institute of Neuroscience, University of Barcelona (NeuroUB), Barcelona, Spain.
Green Accepted
|