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

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.

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

10.1101/2020.10.27.356881 ◽

2020 ◽

Author(s):

D. Puigoriol-Illamola ◽

J. Companys-Alemany ◽

N. Homer ◽

R. Leiva ◽

S. Vázquez ◽

...

Keyword(s):

Cognitive Performance ◽

Molecular Mechanisms ◽

Target Engagement ◽

App Processing ◽

Beneficial Effects ◽

Cognitive Improvement ◽

Age Related ◽

The One ◽

Age Related Cognitive Decline ◽

Samp8 Mice

1.AbstractTaking 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 the inhibition of this enzyme with reduction of 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 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 amyloidogenic APP processing pathway 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, but restored 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.

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CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function

Nature Communications ◽

10.1038/s41467-021-24056-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Saumil Sethna ◽

Patrick A. Scott ◽

Arnaud P. J. Giese ◽

Todd Duncan ◽

Xiaoying Jian ◽

...

Keyword(s):

Visual Function ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Negative Regulator ◽

Age Related Macular Degeneration ◽

Age Related ◽

Mtorc1 Signaling ◽

Marked Accumulation

AbstractAge-related macular degeneration (AMD) is a multifactorial neurodegenerative disorder. Although molecular mechanisms remain elusive, deficits in autophagy have been associated with AMD. Here we show that deficiency of calcium and integrin binding protein 2 (CIB2) in mice, leads to age-related pathologies, including sub-retinal pigment epithelium (RPE) deposits, marked accumulation of drusen markers APOE, C3, Aβ, and esterified cholesterol, and impaired visual function, which can be rescued using exogenous retinoids. Cib2 mutant mice exhibit reduced lysosomal capacity and autophagic clearance, and increased mTORC1 signaling—a negative regulator of autophagy. We observe concordant molecular deficits in dry-AMD RPE/choroid post-mortem human tissues. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to ‘nucleotide empty’ or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts downregulates hyperactive mTORC1 signaling. Thus, our findings have significant implications for treatment of AMD and other mTORC1 hyperactivity-associated disorders.

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Neurocognitive Aging and Functional Connectivity Using Functional Magnetic Resonance Imaging

Oxford Research Encyclopedia of Psychology ◽

10.1093/acrefore/9780190236557.013.385 ◽

2018 ◽

Author(s):

Hana Burianová

Keyword(s):

Functional Connectivity ◽

Cognitive Processes ◽

Large Scale ◽

Healthy Aging ◽

Brain Activity ◽

Brain Regions ◽

Effective Strategies ◽

Cognitive Improvement ◽

Age Related ◽

Neurocognitive Aging

Determining the mechanisms that underlie neurocognitive aging, such as compensation or dedifferentiation, and facilitating the development of effective strategies for cognitive improvement is essential due to the steadily rising aging population. One approach to study the characteristics of healthy aging comprises the assessment of functional connectivity, delineating markers of age-related neurocognitive plasticity. Functional connectivity paradigms characterize complex one-to-many (or many-to-many) structure–function relations, as higher-level cognitive processes are mediated by the interaction among a number of functionally related neural areas rather than localized to discrete brain regions. Task-related or resting-state interregional correlations of brain activity have been used as reliable indices of functional connectivity, delineating age-related alterations in a number of large-scale brain networks, which subserve attention, working memory, episodic retrieval, and task-switching. Together with behavioral and regional activation studies, connectivity studies and modeling approaches have contributed to our understanding of the mechanisms of age-related reorganization of distributed functional networks; specifically, reduced neural specificity (dedifferentiation) and associated impairment in inhibitory control and compensatory neural recruitment.

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Acute ketamine restores deficits in glutamate release and related molecular mechanisms induced by chronic mild stress in vulnerable rats

European Neuropsychopharmacology ◽

10.1016/s0924-977x(16)31713-8 ◽

2016 ◽

Vol 26 ◽

pp. S624

Author(s):

P. Tornese ◽

L. Musazzi ◽

N. Sala ◽

M. Seguini ◽

M. Milanese ◽

...

Keyword(s):

Molecular Mechanisms ◽

Glutamate Release ◽

Chronic Mild Stress ◽

Mild Stress

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Timing matters: the interval between acute stressors within chronic mild stress modifies behavioral and physiologic stress responses in male rats

Stress ◽

10.1080/10253890.2018.1459557 ◽

2018 ◽

Vol 21 (5) ◽

pp. 453-463 ◽

Cited By ~ 9

Author(s):

Sonia A. Cavigelli ◽

Alexander D. Bao ◽

Rebecca A. Bourne ◽

Michael J. Caruso ◽

Jasmine I. Caulfield ◽

...

Keyword(s):

Stress Responses ◽

Chronic Mild Stress ◽

Male Rats ◽

Mild Stress

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Age-related changes in microglial physiology: the role for healthy brain ageing and neurodegenerative disorders

e-Neuroforum ◽

10.1515/nf-2016-a057 ◽

2017 ◽

Vol 23 (4) ◽

Cited By ~ 4

Author(s):

Olga Garaschuk

Keyword(s):

Neurodegenerative Disorders ◽

Healthy Aging ◽

Molecular Mechanisms ◽

Brain Parenchyma ◽

Immune Defense ◽

Synaptic Activity ◽

Mammalian Brain ◽

Age Related ◽

Brain Ageing ◽

The Brain

AbstractMicroglia are the main immune cells of the brain contributing, however, not only to brain’s immune defense but also to many basic housekeeping functions such as development and maintenance of functional neural networks, provision of trophic support for surrounding neurons, monitoring and modulating the levels of synaptic activity, cleaning of accumulating extracellular debris and repairing microdamages of the brain parenchyma. As a consequence, age-related alterations in microglial function likely have a manifold impact on brain’s physiology. In this review, I discuss the recent data about physiological properties of microglia in the adult mammalian brain; changes observed in the brain innate immune system during healthy aging and the probable biological mechanisms responsible for them as well as changes occurring in humans and mice during age-related neurodegenerative disorders along with underlying cellular/molecular mechanisms. Together these data provide a new conceptual framework for thinking about the role of microglia in the context of age-mediated brain dysfunction.

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Noggin rescues age-related stem cell loss in the brain of senescent mice with neurodegenerative pathology

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1813205115 ◽

2018 ◽

Vol 115 (45) ◽

pp. 11625-11630 ◽

Cited By ~ 16

Author(s):

María Díaz-Moreno ◽

Tomás Armenteros ◽

Simona Gradari ◽

Rafael Hortigüela ◽

Laura García-Corzo ◽

...

Keyword(s):

Healthy Aging ◽

Late Onset ◽

Hippocampal Neurogenesis ◽

Bmp Signaling ◽

In Vitro Assays ◽

Age Related ◽

Samp8 Mice ◽

The Brain

Increasing age is the greatest known risk factor for the sporadic late-onset forms of neurodegenerative disorders such as Alzheimer’s disease (AD). One of the brain regions most severely affected in AD is the hippocampus, a privileged structure that contains adult neural stem cells (NSCs) with neurogenic capacity. Hippocampal neurogenesis decreases during aging and the decrease is exacerbated in AD, but the mechanistic causes underlying this progressive decline remain largely unexplored. We here investigated the effect of age on NSCs and neurogenesis by analyzing the senescence accelerated mouse prone 8 (SAMP8) strain, a nontransgenic short-lived strain that spontaneously develops a pathological profile similar to that of AD and that has been employed as a model system to study the transition from healthy aging to neurodegeneration. We show that SAMP8 mice display an accelerated loss of the NSC pool that coincides with an aberrant rise in BMP6 protein, enhanced canonical BMP signaling, and increased astroglial differentiation. In vitro assays demonstrate that BMP6 severely impairs NSC expansion and promotes NSC differentiation into postmitotic astrocytes. Blocking the dysregulation of the BMP pathway and its progliogenic effect in vivo by intracranial delivery of the antagonist Noggin restores hippocampal NSC numbers, neurogenesis, and behavior in SAMP8 mice. Thus, manipulating the local microenvironment of the NSC pool counteracts hippocampal dysfunction in pathological aging. Our results shed light on interventions that may allow taking advantage of the brain’s natural plastic capacity to enhance cognitive function in late adulthood and in chronic neurodegenerative diseases such as AD.

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Electroacupuncture Restores 5-HT System Deficit in Chronic Mild Stress-Induced Depressed Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/7950635 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Dongmei Duan ◽

Ya Tu ◽

Xiuyan Yang ◽

Ping Liu

Keyword(s):

Molecular Mechanisms ◽

Tryptophan Hydroxylase ◽

Chronic Mild Stress ◽

Monoamine Oxidase A ◽

Synthesis Process ◽

Mild Stress ◽

Mao A ◽

Antidepressant Efficacy ◽

Hydroxyindoleacetic Acid ◽

Behavior Of Rats

Objective.The current study is designed to investigate the antidepressant efficacy of electroacupuncture (EA) treatment by evaluating its effect on the synthesis, metabolism, reuptake, and receptors of 5-hydroxytryptamine (5-HT), so as to clarify the molecular mechanisms of EA for antidepression.Materials and Methods.Solitary combined with the chronic unpredictable mild stress (CUMS) was used to establish the rat model with depression. The depressed rats were supplied with EA treatment for 4 weeks, and the behavior change and the following indices including 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), monoamine oxidase A (MAO-A), tryptophan hydroxylase (TPH), 5-HT transporter (SERT), 5-HT1A, and 5-HT2A in hippocampus and prefrontal cortex were examined.Results.EA treatment significantly improved the behavior of rats and increased 5-HT level in hippocampus of depressed rats. Similarly, EA treatment could significantly increase protein and mRNA expression of TPH and 5-HT1A during 5-HT synthesis process in hippocampus of depressed rats. However, EA treatment had no effect on the activity of MAO-A and the expression of SERT protein and mRNA.Conclusion.Antidepressant efficacy of EA treatment can be accomplished through enhancing 5-HT synthesis, upregulating 5-HT1A level, and improving 5-HT content in brain and synaptic gaps.

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

10.20944/preprints202001.0244.v1 ◽

2020 ◽

Author(s):

Dolors Puigoriol-Illamola ◽

Mirna Martínez-Damas ◽

Christian Griñán-Ferré ◽

Mercè Pallàs

Keyword(s):

Cognitive Performance ◽

Posttranslational Modifications ◽

Healthy Aging ◽

Glycogen Synthase ◽

Chronic Mild Stress ◽

Modern Society ◽

Public Healthcare ◽

Mild Stress ◽

Epigenetic Mechanisms ◽

Protein Levels

Cognitive and behavioural disturbances are growing public healthcare issue for the modern society, as stressful lifestyle is becoming more and more common. Besides, several pieces of evidence state that environment is crucial in the development of several diseases as well as compromising healthy aging. Therefore, it is important to study the effects of stress on cognition and its relationship with aging. To address these queries, Chronic Mild Stress (CMS) paradigm was used in the senescence-accelerated mouse prone 8 (SAMP8) and resistant 1 (SAMR1). On one hand, we determined the changes produced in the three main epigenetic marks after 4 weeks of CMS treatment, such as a reduction in histone posttranslational modifications and DNA methylation, and up-regulation or down-regulation of several miRNA involved in different cellular processes in mice. In addition, CMS treatment induced reactive oxygen species (ROS) accumulation and loss of antioxidant defence mechanisms, as well as inflammatory signalling activation through NF-κB pathway and astrogliosis markers, like Gfap. Remarkably, CMS altered mTORC1 signalling in both strains, decreasing autophagy only in SAMR1 mice. We found a decrease in glycogen synthase kinase 3 β (GSK-3β) inactivation, hyperphosphorylation of Tau and an increase in sAPPβ protein levels in mice under CMS. Moreover, reduction in the non-amyloidogenic secretase ADAM10 protein levels was found in SAMR1 CMS group. Consequently, detrimental effects on behaviour and cognitive performance were detected in CMS treated mice, affecting mainly SAMR1 mice, promoting a turning to SAMP8 phenotype. In conclusion, CMS is a feasible intervention to understand the influence of stress on epigenetic mechanisms underlying cognition and accelerating senescence.

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