The Contribution of Epigenetic Inheritance Processes on Age-Related Cognitive Decline and Alzheimer's Disease

: During the last years, epigenetic processes have emerged as important factors for many neurodegenerative diseases, such as Alzheimer's disease (AD). These complex diseases seem to have a heritable component; however, genome-wide association studies failed to identify the genetic loci involved in the etiology. So, how can these changes be transmitted from one generation to the next? Answering this question would allow us to understand how the environment can affect human populations for multiple generations and explain the high prevalence of neurodegenerative diseases, such as AD. This review pays particular attention to the relationship among epigenetics, cognition, and neurodegeneration across generations, deepening the understanding of the relevance of heritability in neurodegenerative diseases. We highlight some recent examples of EI induced by experiences, focusing on their contribution of processes in learning and memory to point out new targets for therapeutic interventions. Here, we first describe the prominent role of epigenetic factors in memory processing. Then, we briefly discuss aspects of EI. Additionally, we summarize evidence of how epigenetic marks inherited by experience and/or environmental stimuli contribute to cognitive status offspring since better knowledge of EI can provide clues in the appearance and development of age-related cognitive decline and AD

Superancianos con superneuronas: ¿por qué hay cerebros que desafían el paso del tiempo?

Los llamados superancianos son las personas con más de 80 años cuyas capacidades cognitivas corresponden a las de alguien 20 o 30 años más joven. Los científicos acaban de descubrir que tienen neuronas más grandes de lo normal en cierta parte de su cerebro

Epigenetic mechanisms underlying cognitive impairment and Alzheimer disease hallmarks in 5XFAD mice

5XFAD is an early-onset mouse transgenic model of Alzheimer disease (AD). Up to now there are no studies that focus on the epigenetic changes produced as a result of Aß-42 accumulation and the possible involvement in the different expression of related AD-genes. Under several behavioral and cognition test, we found impairment in memory and psychoemotional changes in female 5XFAD mice in reference to wild type that worsens with age. Cognitive changes correlated with alterations on protein level analysis and gene expression of markers related with tau aberrant phosphorylation, amyloidogenic pathway (APP, BACE1), Oxidative Stress (iNOS, Aldh2) and inflammation (astrogliosis, TNF-¿ and IL-6); no changes were found in non-amyloidogenic pathway indicators such as ADAM10. Epigenetics changes as higher CpG methylation and transcriptional changes in DNA methyltransferases (DNMTs) family were found. Dnmt1 increases in younger 5XFAD and Dnmt3a and b high levels in the oldest transgenic mice. Similar pattern was found with histone methyltransferases such as Jarid1a andG9a. Histone deacetylase 2 (Hdac2) or Sirt6, both related with cognition and memory, presented a similar pattern. Taken together, these hallmarks presented by the 5XFAD model prompted its use in assessing different potential therapeutic interventions based on epigenetic targets after earlier amyloid deposition.This study was supported by Spanish MINECO, and the European Regional Development Funds (SAF-2012- 39852, BFU2013-48822-R and CSD2010-00045). CGF, AC, and MP belong to 2014 SGR 525; and SS and CS to 2014 SGR 625.Peer Reviewe

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

Cognitive and behavioural disturbances are a 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) damage accumulation and loss of antioxidant defence mechanisms, as well as inflammatory signalling activation through NF-kappa B 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 beta (GSK-3beta) inactivation, hyperphosphorylation of Tau and an increase in sAPPbeta 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

Inhibition of 11β-HSD1, a key enzyme in the stress management, improves cognition by RL-118 drug treatment

In recent years, stress and stress-coping mechanisms constitute a growing public healthcare issue concerning modern society. Experiencing stress engenders a great complex mechanism named stress response, which consists of a rapid release of catecholamines by the sympathetic nervous system, followed by a slower response in which hormones, mainly glucocorticoids (GCs), are synthesized and released to the bloodstream. Once the stressful stimulus is perceived, the hypothalamus secretes the corticotropin-releasing hormone (CRH), which acts on the pituitary gland, activating the release of adrenocorticotropic hormone (ACTH) that binds to the adrenal glands, promoting GC secretion and conforming the hypothalamus-hypophysis-adrenal (HPA) axis. Under normal conditions, GC secretion follows a robust circadian oscillation with a peak around the onset of the active period of the day, i.e., about 1 hour before arising [1]. This basal level of GC secretion is important in exerting tonic effects upon metabolic, immune and neuronal pathways, involving gluconeogenesis stimulation, protein degradation and lipolysis increase, priming of neural regions involved in sensory processing, attention and adaptive responding, as well as accounting for immunosuppressive and anti-inflammatory actions [2]. However, when stressful exposure is prolonged, the HPA axis deregulates and GC secretion is exacerbated. This excessive GC concentration leads to several metabolic, neurological and behavioral alterations, notably cognitive impairment and affective dysfunctions. GC activity is regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, which inhibition has been proved to restore metabolic and behavioral alterations, as well as enhance cognitive abilities. In fact, cortisol, the main active GC in humans, has been postulated as a potential biomarker for neurodegenerative disorders [3], like Alzheimer's disease (AD) in which aging is the major risk factor. Although it is completely assumed that stress directly influences the frailty phenotype in aged people, there are strikingly few measures to restrain stressful lifestyles in order to reduce the progression of pathological towards successful aging. Therefore, the study of stress effects on cognition and its relationship with aging is of the utmost importance to unveil what challenged we might have to cope with as a society in a not so far future

The pleiotropic neuroprotective effects of resveratrol in cognitive decline and Alzheimer’s disease pathology: From antioxidant to epigenetic therapy

Antioxidants; Neurodegeneration; ResveratrolAntioxidantes; Neurodegeneración; ResveratrolAntioxidants; Neurodegeneració; ResveratrolWhile the elderly segment of the population continues growing in importance, neurodegenerative diseases increase exponentially. Lifestyle factors such as nutrition, exercise, and education, among others, influence ageing progression, throughout life. Notably, the Central Nervous System (CNS) can benefit from nutritional strategies and dietary interventions that prevent signs of senescence, such as cognitive decline or neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s Disease. The dietary polyphenol Resveratrol (RV) possesses antioxidant and cytoprotective effects, producing neuroprotection in several organisms. The oxidative stress (OS) occurs because of Reactive oxygen species (ROS) accumulation that has been proposed to explain the cause of the ageing. One of the most harmful effects of ROS in the cell is DNA damage. Nevertheless, there is also evidence demonstrating that OS can produce other molecular changes such as mitochondrial dysfunction, inflammation, apoptosis, and epigenetic modifications, among others. Interestingly, the dietary polyphenol RV is a potent antioxidant and possesses pleiotropic actions, exerting its activity through various molecular pathways. In addition, recent evidence has shown that RV mediates epigenetic changes involved in ageing and the function of the CNS that persists across generations. Furthermore, it has been demonstrated that RV interacts with gut microbiota, showing modifications in bacterial composition associated with beneficial effects. In this review, we give a comprehensive overview of the main mechanisms of action of RV in different experimental models, including clinical trials and discuss how the interconnection of these molecular events could explain the neuroprotective effects induced by RV.This study was supported by the Ministerio de Economía, Industria y Competitividad (Agencia Estatal de Investigación, AEI) and Fondo Europeo de Desarrollo Regional (MINECO-FEDER) (PID2019-106285RB and PCIN-2015-229, and Generalitat de Catalunya (2017 SGR 106) to M.P. The work was funded by grants from the Hungarian Science Foundation (OTKA K 116525), and from the Semmelweis University (STIA-KFI-2020/132257/AOMBT/2020) to C.S

Adenosine and Metabotropic Glutamate Receptors Are Present in Blood Serum and Exosomes from SAMP8 Mice: Modulation by Aging and Resveratrol

Adenosine (ARs) and metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors (GPCRs) that are modulated in the brain of SAMP8 mice, an animal model of Alzheimer's disease (AD). In the present work, it is shown the presence of ARs and mGluRs in blood serum and derived exosomes from SAMP8 mice as well as its possible modulation by aging and resveratrol (RSV) consumption. In blood serum, adenosineA1 andA2A receptors remained unaltered from 5 to 7 months of age. However, an age-related decrease in adenosine level was observed, while 50-Nucleotidase activity was not modulated. Regarding the glutamatergic system, it was observed a decrease in mGluR5 density and glutamate levels in older mice. In addition, dietary RSV supplementation caused an age-dependent modulation in both adenosinergic and glutamatergic systems. These GPCRs were also found in blood serum-derived exosomes, which might suggest that these receptors could be released into circulation via exosomes. Interestingly, changes elicited by age and RSV supplementation on mGluR5 density, and adenosine and glutamate levels were similar to that detected in whole-brain. Therefore, we might suggest that the quantification of these receptors, and their corresponding endogenous ligands, in blood serum could have predictive value for early diagnosis in combination with other distinctive hallmarks of AD

Synergistic Neuroprotective Effects of a Natural Product Mixture against AD Hallmarks and Cognitive Decline in Caenorhabditis elegans and an SAMP8 Mice Model

The study of different natural products can provide a wealth of bioactive compounds, and more interestingly, their combination can exert a new strategy for several neurodegenerative diseases with major public health importance, such as Alzheimer's disease (AD). Here, we investigated the synergistic neuroprotective effects of a mixed extract composed of docosahexaenoic acid, Ginkgo biloba, D-pinitol, and ursolic acid in several transgenic Caenorhabditis elegans (C. elegans) and a senescence-accelerated prone mice 8 (SAMP8) model. First, we found a significantly higher survival percentage in the C. elegans group treated with the natural product mixture compared to the single extract-treated groups. Likewise, we found a significantly increased lifespan in group of C. elegans treated with the natural product mixture compared to the other groups, suggesting synergistic effects. Remarkably, we determined a significant reduction in Aβ plaque accumulation in the group of C. elegans treated with the natural product mixture compared to the other groups, confirming synergy. Finally, we demonstrated better cognitive performance in the group treated with the natural product mixture in both AD models (neuronal Aβ C. elegans strain CL2355 and the SAMP8 mice model), confirming the molecular results and unraveling the synergist effects of this combination. Therefore, our results proved the potential of this new natural product mixture for AD therapeutic strategies

Chromatin modifiers MET-2 and SET-25 are required for behavioural and molecular inheritance after early-life toxic stress in C. elegans

Stress exposure early in life is associated with behavioural and bodily changes that can develop several neuropsychiatric illnesses such as dementia. Experiences during the critical perinatal period form permanent, imprinted memories that can persistently alter expression levels of key genes through epigenetic marking, which can underpin changes in behaviour, molecular and stress responsivity throughout later life, including the next generations. Besides, this implies that gene by environment interactions (such as through epigenetic modifications) may be involved in the onset of these phenotypes. Although there are a number of studies in this field, there are still research gaps. For this reason, understanding the molecular mechanisms underlying the enduring effects of early-life stress is an important research area of the neuroscience. The aim of this project is to determine the behavioural and molecular changes and if there are changes in the epigenetic enzymes that can explain in part this phenomenon. Here using an experimental paradigm, we report that in response to early-life stresses, Caenorhabditis elegans nematodes form an imprinted behavioural and cellular defence memory. We show that exposing newly-born worms to toxic antimycin A exposure or repeated exposure, promotes aversive behaviour through chemotaxis assay and stimulates the expression of the hsp-6 enzyme a toxinspecific cytoprotective. Learned adult defences require memory formation during the L1 larval stage and do not appear to confer increased protection against the toxin. We found that aversive behaviour is inherited only to the F1 generation after 1 exposure to the toxic or can be passed to the F4 generation after 4 exposures to the toxic. At the molecular level, we found changes in the chromatin modifiers MET-2 and SET-25 as well as their target gene SKN-1 until the F3 generation after 1 exposure to the toxic or until the F5 generation after 4 exposures to the toxic stress. Furthermore, we found changes in the lifespan after 1 exposure in the F1 until F3 generations as well as in the F1 until F5 generations after 4 exposures to the toxic stimulus. Regarding the oxidative stress response, we found changes in the same generations after 1 exposure or after 4 exposures to early life toxic stress. Thus, exposure of Caenorhabditis elegans to toxic stresses in the critical period elicits adaptive behavioural and cytoprotective responses as we all as promote changes in the health outcomes, demonstrating a wide range of alterations that can appear after an early-life harmful stimulus. Likewise, we can conclude that these results are orchestrated by SET-25 pathway through SKN-1 transcription factor, which forms imprinted aversive behaviour and imprints a cytoprotective memory in the adulthood and the successive generations. These results, open a new avenue for new epigenetic therapies for neuropsychiatric disorders through chromati