Chronic Mild Stress Modified Epigenetic Mechanisms Leading to Accelerated Senescence and Impaired Cognitive Performance in Mice

Puigoriol-Illamola, Dolors; Martínez-Damas, Mirna; Pallàs, Mercè

doi:10.3390/ijms21031154

Cited by 14 publications

(24 citation statements)

References 50 publications

(71 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additional data (Kadmiel & Cidlowski, 2013;Picard et al, 2018;Puigoriol-Illamola et al, 2020a) report that a stressful environment affects oxidative balance. In normal conditions, pro-oxidant molecules and antioxidant defence mechanisms are balanced; however, under the presence of chronic stressors as well as along aging and in several disorders, there is a decrease in the capacity of the antioxidant enzymes allowing ROS accumulation and eventually causing cellular damage and finally dysfunction of the system (Griñán-Ferré et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…For 4 weeks, mice were daily exposed to various randomly scheduled, low-intensity environmental stressors. The number and the type of stressful stimuli applied changed everyday as well as the sequence of the stressors in order to guarantee the degree of unpredictability (Puigoriol-Illamola et al, 2020a). Stressful stimuli included 2 h of physical restraint, 24 h of sawdust removal, 24 h of food deprivation, 24 h of water deprivation, 24 h of wet bedding, 1 min of tail nipping at 1 cm from the tip of the tail and overnight illumination.…”

Section: Chronic Mild Stress Treatmentmentioning

confidence: 99%

“…Several studies suggest that environmental stressors influence hypothalamic-pituitaryadrenal (HPA) axis activity and behaviour by altering the methylation status of key genes concerned with the regulation of the stress response (Harman & Martín, 2019;Sotiropoulous et al, 2008). Recent evidence has demonstrated significant associations between epigenetic alterations and stress showing that under chronic stressors influence, histone acetylation and DNA methylation are decreased, among others (Harman & Martín, 2019;Puigoriol-Illamola et al, 2020a).…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, recent clinical studies suggest that GCs are implicated in the pathogenesis and/or progression of AD (Sotiropoulous et al, 2011). In particular, chronic stress has been associated with increased Aβ deposits and hyperphosphorylated Tau (Bisht et al, 2018;Puigoriol-Illamola et al,2020a). In view of these affections, it is important to note that stressful events can have long-term consequences for the immune system.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, GCs are also involved in the regulation of cell fate, modulating pro-/antiapoptotic mechanisms and survival proteins, such as BDNF, CREB, Bcl2 and NCAM, so that may exert significant influence over neuroplasticity (Pittenger & Duman, 2008;Sandi, 2004Sandi, , et al, 2013Sotiropoulous et al, 2008;Wang et al, 2016). Noteworthy for cell survival and longevity, autophagy activation becomes crucial, as it participates in the elimination of disrupted proteins and is implied in the maintenance of cellular homeostasis (Puigoriol-Illamola et al, 2020a).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

RL-118 and 11β-HSD1 target engagement through TAPS assay: behaviour and molecular analysis

Puigoriol-Illamola

Companys-Alemany

McGuire

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Taking into consideration the convergence of ageing, stress and neurodegenerative diseases, such as AD, there is impaired GC signalling. Therefore, the study of GC-mediated stress response to chronic moderate stressful situations, as account in daily life, becomes of huge interest to design pharmacological strategies to prevent neurodegeneration. To address this issue, SAMP8 were exposed for 4 weeks to the CMS paradigm and treated with RL-118, an 11β-HSD1 inhibitor. In fact, several pieces of evidence link CMS exposure to reduced cognitive performance, while inhibition of 11β-HSD1 has been associated with reduction of GC activity and cognitive improvement. The aim of this project was to assess whether RL-118 treatment could restore the deleterious effects of CMS on cognition and behavioural abilities, but also on molecular mechanisms that compromise healthy ageing in SAMP8 mice. On the one hand, we determined the target engagement between RL-118 and 11β-HSD1. Therefore all the beneficial effects previously described in SAMP8 treated with the drug can undoubtedly be attributed to the inhibition of this enzyme. Besides, herein we observed decreased DNA methylation, hydroxymethylation and histone phosphorylation induced by CMS but, on the contrary, increased after RL-118 treatment. In addition, CMS exposure produced ROS damage accumulation, and increments of pro-oxidant enzymes as well as pro-inflammatory mediators through NF-κB pathway and astrogliosis markers, like Gfap. Of note, those modifications were recovered by 11β-HSD1 inhibition. Remarkably, although CMS altered mTORC1 signalling, autophagy was increased in SAMP8 treated with RL-118 mice. Also, we found that amyloidogenic APP processing pathway was favoured and decreased synaptic plasticity and neuronal remodelling markers in mice under CMS, but changed after RL-118 treatment. In consequence, detrimental effects on behaviour and cognitive performance were detected in CMS exposed mice, although recovered after concomitant 11β-HSD1 inhibition by RL-118. Overall, CMS is a feasible intervention to understand the influence of stress on epigenetic mechanisms underlying cognition and accelerating senescence. However and most important, 11β-HSD1 inhibition through RL-118 turned up to restore the majority of these detrimental effects caused by CMS, indicating that GC excess attenuation may become a potential therapeutic strategy for age-related cognitive decline and AD.

show abstract