‘Innate immune memory’ is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished, training and tolerance, which are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages, microglia, that persists for at least six months. Strikingly, in a mouse model of Alzheimer’s pathology, immune training exacerbates cerebral β-amyloidosis while tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.

Aims Deregulation of epigenetic processes and aberrant gene expression are important mechanisms in heart failure. Here we studied the potential relevance of m6A RNA methylation in heart failure development. Methods and results We analysed m6A RNA methylation via next‐generation sequencing. We found that approximately one quarter of the transcripts in the healthy mouse and human heart exhibit m6A RNA methylation. During progression to heart failure we observed that changes in m6A RNA methylation exceed changes in gene expression both in mouse and human. RNAs with altered m6A RNA methylation were mainly linked to metabolic and regulatory pathways, while changes in RNA expression level mainly represented changes in structural plasticity. Mechanistically, we could link m6A RNA methylation to altered RNA translation and protein production. Interestingly, differentially methylated but not differentially expressed RNAs showed differential polysomal occupancy, indicating transcription‐independent modulation of translation. Furthermore, mice with a cardiomyocyte restricted knockout of the RNA demethylase Fto exhibited an impaired cardiac function compared to control mice. Conclusions We could show that m6A landscape is altered in heart hypertrophy and heart failure. m6A RNA methylation changes lead to changes in protein abundance, unconnected to mRNA levels. This uncovers a new transcription‐independent mechanisms of translation regulation. Therefore, our data suggest that modulation of epitranscriptomic processes such as m6A methylation might be an interesting target for therapeutic interventions.

SummaryPhysical exercise in combination with cognitive training is known to enhance synaptic plasticity, learning, and memory and lower the risk for various complex diseases including Alzheimer’s disease. Here, we show that exposure of adult male mice to an environmental enrichment paradigm leads to enhancement of synaptic plasticity and cognition also in the next generation. We show that this effect is mediated through sperm RNA and especially miRs 212/132. In conclusion, our study reports intergenerational inheritance of an acquired cognitive benefit and points to specific miRs as candidates mechanistically involved in this type of transmission.

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While some individuals age without pathological memory impairments, others develop age‐associated cognitive diseases. Since changes in cognitive function develop slowly over time in these patients, they are often diagnosed at an advanced stage of molecular pathology, a time point when causative treatments fail. Thus, there is great need for the identification of inexpensive and minimal invasive approaches that could be used for screening with the aim to identify individuals at risk for cognitive decline that can then undergo further diagnostics and eventually stratified therapies. In this study, we use an integrative approach combining the analysis of human data and mechanistic studies in model systems to identify a circulating 3‐microRNA signature that reflects key processes linked to neural homeostasis and inform about cognitive status. We furthermore provide evidence that expression changes in this signature represent multiple mechanisms deregulated in the aging and diseased brain and are a suitable target for RNA therapeutics.

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a b s t r a c tAcetylcholine-esterase (AchE) inhibitors are one of the most potent drug molecules against Alzheimer's disease (AD). But, patients treated with current AchE inhibitors often experience severe side effects. Quercetin is a plant flavonoid compound which can act as AchE inhibitor and it may be a better alternative to current AchE inhibitors in terms of effectiveness with no or fewer side effects. Aims: The aim of the study was to compare quercetin with conventional AchE inhibitors to search for a better drug candidate. Methods and materials: Physico-chemical properties of conventional drugs and quercetin were predicted using bioinformatics tools. Molecular docking of these compounds on the active site of AchE was performed using AutoDock and comparative analysis was performed. Later, modification on the basic structure of quercetin with different functional groups was done to perform QSAR analysis. Result and discussion: Quercetin showed a similar drug likeness score to the conventional drugs. The binding strength for quercetin in the active site of the enzyme was À8.8 kcal/mol, which was considerably higher than binding scores for some of the drugs such as donepezil (binding score À7.9 kcal/mol). Fifteen hydrogen bonds were predicted between quercetin and the enzyme whereas conventional drugs had fewer or even no hydrogen bonds. It implies that quercetin can act as a better inhibitor than conventional drugs. To find out even better inhibitor, similar structures of quercetin were searched through SIMCOMP database and a methylation in the 4-OH position of the molecule showed better binding affinity than parent quercetin. Quantitative structure activity relationship study indicated that O-4 methylation was specifically responsible for better affinity. Conclusion: This in silico study has conclusively predicted the superiority of the natural compound quercetin over the conventional drugs as AchE inhibitor and it sets the need for further in-vitro study of this compound in future.

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