Abstract
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 11β-HSD type 1 (11β-HSD1) with cognitive improvement. In the present study, we investigated the beneficial effects of 11β-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 11β-HSD1 and glucocorticoid receptor (GR) protein levels. Furthermore, specific modifications in the FGF21 activation after treatment with 11β-HSD1i, RL-118, which induced changes in SIRT1/PGC1α/AMPKα 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 11β-HSD1i. Remarkably, treatment with 11β-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 (GSK3β) activation, Tau hyperphosphorylation, BACE1 protein levels and the product β-CTF were found. Increases in the non-amyloidogenic secretase ADAM10 protein levels and the product sAPPα 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 11β-HSD1i for the treatment of age-related cognitive decline and AD.
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Funding
This study was supported by Ministerio de Economía y Competitividad of Spain and FEDER(SAF2016-77703 to MP and SAF2017-82771 to SV, and SAF2015-64146-R to MVC) and 2017SGR106 (AGAUR, Catalonia). Financial support was provided for D.P.I. and R.L. (FPU program). ACCIÓ (Generalitat de Catalunya) provided financial support (Programa Nuclis, RD14-1-0057, SAFNAD).
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Puigoriol-Illamola, D., Leiva, R., Vázquez-Carrera, M. et al. 11β-HSD1 Inhibition Rescues SAMP8 Cognitive Impairment Induced by Metabolic Stress. Mol Neurobiol 57, 551–565 (2020). https://doi.org/10.1007/s12035-019-01708-4
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DOI: https://doi.org/10.1007/s12035-019-01708-4