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

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.

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

2021 ◽  
Vol 14 (10) ◽  
pp. 1040
Author(s):  
Dolors Puigoriol-Illamola ◽  
Júlia Companys-Alemany ◽  
Kris McGuire ◽  
Natalie Z. M. Homer ◽  
Rosana Leiva ◽  
...  
Keyword(s):  
Stress Responses ◽  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Chronic Mild Stress ◽  
Mild Stress ◽  
Cognitive Improvement ◽  
Age Related ◽  
Mtorc1 Signaling ◽  
Cognitive Disturbances ◽  
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.

scholarly journals Multimodal measurement approach to identify individuals with mild cognitive impairment: study protocol for a cross-sectional trial

BMJ Open ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. e046879
Author(s):  
Bernhard Grässler ◽  
Fabian Herold ◽  
Milos Dordevic ◽  
Tariq Ali Gujar ◽  
Sabine Darius ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Statistical Analysis ◽  
Cognitive Decline ◽  
Cognitive Performance ◽  
Classification Accuracy ◽  
Multimodal Approach ◽  
Cross Sectional ◽  
Age Related ◽  
Age Related Cognitive Decline

IntroductionThe diagnosis of mild cognitive impairment (MCI), that is, the transitory phase between normal age-related cognitive decline and dementia, remains a challenging task. It was observed that a multimodal approach (simultaneous analysis of several complementary modalities) can improve the classification accuracy. We will combine three noninvasive measurement modalities: functional near-infrared spectroscopy (fNIRS), electroencephalography and heart rate variability via ECG. Our aim is to explore neurophysiological correlates of cognitive performance and whether our multimodal approach can aid in early identification of individuals with MCI.Methods and analysisThis study will be a cross-sectional with patients with MCI and healthy controls (HC). The neurophysiological signals will be measured during rest and while performing cognitive tasks: (1) Stroop, (2) N-back and (3) verbal fluency test (VFT). Main aims of statistical analysis are to (1) determine the differences in neurophysiological responses of HC and MCI, (2) investigate relationships between measures of cognitive performance and neurophysiological responses and (3) investigate whether the classification accuracy can be improved by using our multimodal approach. To meet these targets, statistical analysis will include machine learning approaches.This is, to the best of our knowledge, the first study that applies simultaneously these three modalities in MCI and HC. We hypothesise that the multimodal approach improves the classification accuracy between HC and MCI as compared with a unimodal approach. If our hypothesis is verified, this study paves the way for additional research on multimodal approaches for dementia research and fosters the exploration of new biomarkers for an early detection of nonphysiological age-related cognitive decline.Ethics and disseminationEthics approval was obtained from the local Ethics Committee (reference: 83/19). Data will be shared with the scientific community no more than 1 year following completion of study and data assembly.Trial registration numberClinicalTrials.gov, NCT04427436, registered on 10 June 2020, https://clinicaltrials.gov/ct2/show/study/NCT04427436.

scholarly journals Beneficial effects of multisensory and cognitive stimulation on age-related cognitive decline in long-term-care institutions

2014 ◽  
pp. 309 ◽  
Author(s):  
Cristovam Picanço-Diniz ◽  
Thais Cristina Galdino De Oliveira ◽  
Fernanda Cabral Soares ◽  
Liliane Dias E Dias De Macedo ◽  
Domingos Luiz Wanderley Picanco Diniz ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Long Term Care ◽  
Cognitive Stimulation ◽  
Term Care ◽  
Beneficial Effects ◽  
Age Related ◽  
Age Related Cognitive Decline

scholarly journals Individual variation in brain microstructural-cognition relationships in aging

2021 ◽  
Author(s):  
Raihaan Patel ◽  
Clare E. Mackay ◽  
Michelle G. Jansen ◽  
Gabriel A. Devenyi ◽  
M. Clare O’Donoghue ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Cognitive Performance ◽  
Late Life ◽  
Older Age ◽  
Data Driven ◽  
Semantic Fluency ◽  
Cognitive Domains ◽  
Age Related ◽  
Brain Microstructure ◽  
Age Related Cognitive Decline

AbstractWhile all individuals are susceptible to age-related cognitive decline, significant inter- and intra-individual variability exists. However, the sources of this variation remain poorly understood. Here, we examined the association between 30-year trajectories of cognitive decline and multimodal indices of brain microstructure and morphology in older age. We used the Whitehall II Study, an extensively characterised cohort using 3T brain magnetic resonance images acquired at older age (mean age = 69.52 ± 4.9) and 5 repeated cognitive performance assessments between mid-life (mean age = 53.2 ± 4.9 years) and late-life (mean age = 67.7 ± 4.9). Using non-negative matrix factorization, we identified 10 brain microstructural components that integrate measures of cortical thickness, surface area, fractional anisotropy, and mean and radial diffusivities. We observed two modes of variance that describe the association between cognition and brain microstructure. The first describes variations in 5 microstructural components associated with low mid-life performance across multiple cognitive domains, decline in reasoning abilities, but a relative maintenance of lexical and semantic fluency from mid-to-late life. The second describes variations in 5 microstructural components that are associated with low mid-life performance in lexical fluency, semantic fluency and short-term memory performance, but a retention of abilities in multiple domains from mid-to-late life. The extent to which a subject loads onto a latent variables predicts their future cognitive performance 3.2 years later (mean age = 70.87 ± 4.9). This data-driven approach highlights a complex pattern of brain-behavior relationships, wherein the same individuals express both decline and maintenance in function across cognitive domains and in brain structural features.Significance StatementAlthough declines in cognitive performance are an established aspect of aging, inter- and intra-individual variation exists. Nevertheless, the sources of this variation remain unclear. We analyse a unique sample to examine associations between 30-year trajectories of cognitive decline and multimodal indices of brain anatomy in older age. Using data-driven techniques, we find that age-related cognitive decline is not uniform. Instead, each individual expresses a mixture of maintenance and decline across cognitive domains, that are associated with a mixture of preservation and degeneration of brain structure. Further, we find the primary determinants of late-life cognitive performance are mid-life performance and higher brain surface area. These results suggest that early and mid-life preventative measures may be needed to reduce age-related cognitive decline.

scholarly journals Lactobacillus paracasei PS23 Delays Progression of Age-Related Cognitive Decline in Senescence Accelerated Mouse Prone 8 (SAMP8) Mice

Nutrients ◽  
2018 ◽  
Vol 10 (7) ◽  
pp. 894 ◽  
Author(s):  
Shih-Yi Huang ◽  
Li-Han Chen ◽  
Ming-Fu Wang ◽  
Chih-Chieh Hsu ◽  
Ching-Hung Chan ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Brain Dysfunction ◽  
Lactobacillus Paracasei ◽  
Oxidative Enzymes ◽  
Control Group ◽  
Age Related ◽  
Chemotactic Protein ◽  
Age Related Cognitive Decline ◽  
Samp8 Mice ◽  
Senescence Accelerated Mouse

Probiotic supplements are potential therapeutic agents for age-related disorders due to their antioxidant and anti-inflammatory properties. However, the effect of probiotics on age-related brain dysfunction remains unclear. To investigate the effects of Lactobacillus paracasei PS23 (LPPS23) on the progression of age-related cognitive decline, male and female senescence-accelerated mouse prone 8 (SAMP8) mice were divided into two groups (n = 6 each): the control and PS23 groups. From the age of 16 weeks, these groups were given saline and LPPS23, respectively, because SAMP8 mice start aging rapidly after four months of age. After 12 weeks of treatment, we evaluated the effect of LPPS23 by analyzing their appearance, behavior, neural monoamines, anti-oxidative enzymes, and inflammatory cytokines. The PS23 group showed lower scores of senescence and less serious anxiety-like behaviors and memory impairment compared to the control group. The control mice also showed lower levels of neural monoamines in the striatum, hippocampus, and serum. Moreover, LPPS23 induced the anti-oxidative enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx). Higher levels of tumor necrosis factor (TNF)-α and monocyte chemotactic protein-1 (MCP1) and lower levels of interleukin (IL)-10 indicated that LPPS23 modulated the inflammation. Our results suggest that LPPS23 supplements could delay age-related cognitive decline, possibly by preventing oxidation and inflammation and modulating gut–brain axis communication.

scholarly journals Resveratrol Attenuates Copper-Induced Senescence by Improving Cellular Proteostasis

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Liliana Matos ◽  
Alexandra Monteiro Gouveia ◽  
Henrique Almeida
Keyword(s):  
Molecular Mechanisms ◽  
Protein Quality ◽  
Replicative Senescence ◽  
Beneficial Effects ◽  
Cell Dysfunction ◽  
Age Related ◽  
Cell Tissue ◽  
Autophagy Induction ◽  
Human Disorders ◽  
Senescence Associated Genes

Copper sulfate-induced premature senescence (CuSO4-SIPS) consistently mimetized molecular mechanisms of replicative senescence, particularly at the endoplasmic reticulum proteostasis level. In fact, disruption of protein homeostasis has been associated to age-related cell/tissue dysfunction and human disorders susceptibility. Resveratrol is a polyphenolic compound with proved antiaging properties under particular conditions. In this setting, we aimed to evaluate resveratrol ability to attenuate cellular senescence induction and to unravel related molecular mechanisms. Using CuSO4-SIPS WI-38 fibroblasts, resveratrol is shown to attenuate typical senescence alterations on cell morphology, senescence-associated beta-galactosidase activity, and cell proliferation. The mechanisms implicated in this antisenescence effect seem to be independent of senescence-associated genes and proteins regulation but are reliant on cellular proteostasis improvement. In fact, resveratrol supplementation restores copper-induced increased protein content, attenuates BiP level, and reduces carbonylated and polyubiquitinated proteins by autophagy induction. Our data provide compelling evidence for the beneficial effects of resveratrol by mitigating CuSO4-SIPS stressful consequences by the modulation of protein quality control systems. These findings highlight the importance of a balanced cellular proteostasis and add further knowledge on molecular mechanisms mediating resveratrol antisenescence effects. Moreover, they contribute to identifying specific molecular targets whose modulation will prevent age-associated cell dysfunction and improve human healthspan.

scholarly journals Unhappiness, health and cognitive ability in old age

2007 ◽  
Vol 38 (2) ◽  
pp. 229-236 ◽  
Author(s):  
P. Rabbitt ◽  
M. Lunn ◽  
S. Ibrahim ◽  
M. Cobain ◽  
L. McInnes
Keyword(s):  
Life Satisfaction ◽  
Cognitive Performance ◽  
Old Age ◽  
Economic Advantage ◽  
Drop Out ◽  
Cognitive Tasks ◽  
Mental Ability ◽  
Age Related ◽  
New Finding ◽  
Age Related Cognitive Decline

BackgroundTo test whether scores on depression inventories on entry to a longitudinal study predict mental ability over the next 4–16 years.MethodAssociations between scores on the Beck Depression Inventory and on tests of intelligence, vocabulary and memory were analysed in 5070 volunteers aged 49–93 years after differences in prescribed drug consumption, death and drop-out, sex, socio-economic advantage and recruitment cohort effects had also been considered.ResultsOn all cognitive tasks Beck scores on entry, even in the range 0–7 indicating differences in above average contentment, affected overall levels of cognitive performance but not rates of age-related cognitive decline suggesting effects of differences in life satisfaction rather than in depression.ConclusionsA new finding is that, in old age, increments in life satisfaction are associated with better cognitive performance. Implications for interpreting associations between depression inventory scores and cognitive performance in elderly samples are discussed.

Do Professors Better Maintain Cognitive Functioning in Older Age?

GeroPsych ◽  
2019 ◽  
Vol 32 (1) ◽  
pp. 5-17
Author(s):  
Damaris Aschwanden ◽  
Vera Schumacher ◽  
Kathrin Zimmermann ◽  
Christina Werner ◽  
Mathias Allemand ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Cognitive Performance ◽  
Cognitive Aging ◽  
Protective Factor ◽  
Perceptual Speed ◽  
Highly Educated ◽  
Intellectual Engagement ◽  
Age Related ◽  
Average Education ◽  
Age Related Cognitive Decline

Abstract. Research on cognitive aging demonstrates age-related cognitive decline. Education is a protective factor against cognitive decline, but few studies have examined the cognitive development of highly educated individuals. This study compared the cognitive performance and intellectual engagement of retired professors ( N = 47, Mage = 72.9) and individuals with average education ( N = 236, Mage = 72.7) over 5 years. Although the highly educated sample showed better performance in perceptual speed and working memory, cognitive performance was rather stable over time in both samples. Interestingly, high intellectual engagement enabled individuals with average education to keep up with the performance of the highly educated sample on perceptual speed. These findings raise the question whether intellectual engagement is more beneficial than years of education in perceptual speed.

scholarly journals Maternal Resveratrol Supplementation Prevents Cognitive Decline in Senescent Mice Offspring

2019 ◽  
Vol 20 (5) ◽  
pp. 1134 ◽  
Author(s):  
Vanesa Izquierdo ◽  
Verónica Palomera-Ávalos ◽  
Sergio López-Ruiz ◽  
Anna-Maria Canudas ◽  
Mercè Pallàs ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cognitive Decline ◽  
Target Genes ◽  
Epigenetic Inheritance ◽  
Mtor Inhibition ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Age Related ◽  
F2 Generation ◽  
Age Related Cognitive Decline

A variety of environmental factors contribute significantly to age-related cognitive decline and memory impairment in Alzheimer’s Disease (AD) and other neurodegenerative diseases. Nutrition can alter epigenetics, improving health outcomes, which can be transmitted across generations; this process is called epigenetic inheritance. We investigate the beneficial effects of maternal resveratrol supplementation in the direct exposed F1 generation and the transgenerational F2 generation. The offspring was generated from females Senescence Accelerated Mouse-Prone (SAMP8) fed a resveratrol-enriched diet for two months prior to mating. Object novel recognition and Morris Water Maze (MWM) demonstrated improvements in cognition in the 6-month-old F1 and F2 generations from resveratrol fed mothers. A significant increase in global DNA methylation with a decrease in hydroxymethylation in F1 and F2 were found. Accordingly, Dnmt3a/b and Tet2 gene expression changed. Methylation levels of Nrf2 and NF-kβ genes promoters raised in offspring, inducing changes in target genes expression, as well as hydrogen peroxide levels. Offspring that resulted from a resveratrol fed mother showed increase AMPKα activation, mTOR inhibition, and an increase in Pgc-1α gene expression and Beclin-1 protein levels. Endoplasmic reticulum stress sensors were found changed both in F1 and F2 generations. Overall, our results demonstrated that maternal resveratrol supplementation could prevent cognitive impairment in the SAMP8 mice offspring through epigenetic changes and cell signaling pathways.

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