Inhibition of 11β-HSD1 Ameliorates Cognition and Molecular Detrimental Changes after Chronic Mild Stress in SAMP8 Mice

Abstract

Impaired glucocorticoid (GC) signaling is a significant factor in aging, stress, and neurodegenerative diseases such as Alzheimer’s disease. Therefore, the study of GC-mediated stress responses to chronic moderately stressful situations, which occur in daily life, is of huge interest for the design of pharmacological strategies toward the prevention of neurodegeneration. To address this issue, SAMP8 mice were exposed to the chronic mild stress (CMS) paradigm for 4 weeks and treated with RL-118, an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor. The inhibition of this enzyme is linked with a reduction in GC levels and cognitive improvement, while CMS exposure has been associated with reduced cognitive performance. The aim of this project was to assess whether RL-118 treatment could reverse the deleterious effects of CMS on cognition and behavioral abilities and to evaluate the molecular mechanisms that compromise healthy aging in SAMP8 mice. First, we confirmed the target engagement between RL-118 and 11β-HSD1. Additionally, we showed that DNA methylation, hydroxymethylation, and histone phosphorylation were decreased by CMS induction, and increased by RL-118 treatment. In addition, CMS exposure caused the accumulation of reactive oxygen species (ROS)-induced damage and increased pro-oxidant enzymes—as well as pro-inflammatory mediators—through the NF-κB pathway and astrogliosis markers, such as GFAP. Of note, these modifications were reversed by 11β-HSD1 inhibition. Remarkably, although CMS altered mTORC1 signaling, autophagy was increased in the SAMP8 RL-118-treated mice. We also showed an increase in amyloidogenic processes and a decrease in synaptic plasticity and neuronal remodeling markers in mice under CMS, which were consequently modified by RL-118 treatment. In conclusion, 11β-HSD1 inhibition through RL-118 ameliorated the detrimental effects induced by CMS, including epigenetic and cognitive disturbances, indicating that GC-excess attenuation shows potential as a therapeutic strategy for age-related cognitive decline and AD.

Stress and the risk of Alzheimer dementia: Can deconstructed engrams be rebuilt?

“…A newer generation of these inhibitors 99 shows very promising results for ameliorating age-related cognitive impairment. 100 Advances in neuroimaging confirmed penetration and stability of these ligands in the brain despite the regional differences. 101 A new positron emission tomography (PET) ligand revealed that the higher expression of HDS1 protein in the brain, the lower the symptoms in PTSD patients, indicating that complete inhibition of HSD1 might be counterproductive.…”

“…Several clinical trials are either ongoing (NCT03823404, NCT04601038) or stopped due to futility (NCT01137526). A newer generation of these inhibitors 99 shows very promising results for ameliorating age‐related cognitive impairment 100 . Advances in neuroimaging confirmed penetration and stability of these ligands in the brain despite the regional differences 101 .…”

11β‐Hydroxysteroid dehydrogenase and the brain: Not (yet) lost in translation

“…11β‐HSD1 inhibition in aged Tg2576 mice up‐regulates amyloid‐catabolizing insulin‐degrading enzyme [115], itself down‐regulated by glucocorticoids [128]. Another inhibitor, RL‐118, decreases β‐secretase‐1 in stressed mice [129]. Alongside possible reduced glucocorticoid‐driven synthesis of beta‐amyloid and tau [102], such changes could delay pathogenesis.…”

“…In 4‐month‐old, senescence‐prone SAMP8 mice – in which elevated corticosterone levels contribute to cognitive and hippocampal structural deficits [130] – 11β‐HSD1 inhibition (RL‐118) improves cognitive function, increases markers of synaptic function, lowers pathogenic hyperphosphorylated tau and reverses epigenetic changes of stress, reducing DNA methylation and 5‐hydroxymethylation, with transcription‐associated histone modifications, plausibly via lowering of DNA‐methyltransferase‐1 and Tet2 [129]. Moreover, in young SAMP8 mice when fed a high‐fat diet, 11β‐HSD1 inhibition induces FGF21 and the SIRT1/PGC1α/AMPKα nutrient sensor pathway in hippocampal cells alongside cognitive improvements [131], though extrapolation to normal senescence is unexplored.…”

“…Moreover, in young SAMP8 mice when fed a high‐fat diet, 11β‐HSD1 inhibition induces FGF21 and the SIRT1/PGC1α/AMPKα nutrient sensor pathway in hippocampal cells alongside cognitive improvements [131], though extrapolation to normal senescence is unexplored. The inhibitor also reduces reactive oxygen species (ROS), with reduced Nrf2 (a key ROS transcription factor) and iNOS [129]. However, SAMP8 mice are short‐lived (mean lifespan 13 months, around half ‘wild‐type’), have markedly elevated basal corticosterone levels, are susceptible to glucocorticoid‐mediated neuronal death (most strains/species resist this) and exhibit dramatic reductions in circulating corticosterone with 11β‐HSD1 inhibition, unlike most rodents and humans [131].…”