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From development to aging and disease, the brain parenchyma is under the constant threat of debris accumulation, in the form of dead cells and protein aggregates. To prevent garbage buildup, the brain is equipped with efficient phagocytes: the microglia. Microglia are similar, but not identical to other tissue macrophages, and in this review, we will first summarize the differences in the origin, lineage and population maintenance of microglia and macrophages. Then, we will discuss several principles that govern macrophage phagocytosis of apoptotic cells (efferocytosis), including the existence of redundant recognition mechanisms (\"find-me\" and \"eat-me\") that lead to a tight coupling between apoptosis and phagocytosis. We will then describe that resulting from engulfment and degradation of apoptotic cargo, phagocytes undergo an epigenetic, transcriptional and metabolic rewiring that leads to trained immunity, and discuss its relevance for microglia and brain function. In summary, we will show that neuroimmunologists can learn many lessons from the well-developed field of macrophage phagocytosis biology.

The turnover of brain proteins is critical for organism survival, and its perturbations are linked to pathology. Nevertheless, protein lifetimes have been difficult to obtain in vivo. They are readily measured in vitro by feeding cells with isotopically labeled amino acids, followed by mass spectrometry analyses. In vivo proteins are generated from at least two sources: labeled amino acids from the diet, and non-labeled amino acids from the degradation of pre-existing proteins. This renders measurements difficult. Here we solved this problem rigorously with a workflow that combines mouse in vivo isotopic labeling, mass spectrometry, and mathematical modeling. We also established several independent approaches to test and validate the results. This enabled us to measure the accurate lifetimes of ~3500 brain proteins. The high precision of our data provided a large set of biologically significant observations, including pathway-, organelle-, organ-, or cell-specific effects, along with a comprehensive catalog of extremely long-lived proteins (ELLPs). Measuring precise protein turnover rates in animals is technically challenging at the proteomic level. Here, Fornasiero and colleagues use isotopic labeling with mass spectrometry and mathematical modeling to accurately determine protein lifetimes in the mouse brain

The trafficking of AMPA receptors to and from the surface of postsynaptic membranes regulates synaptic strength and underlies learning and memory. Awasthi et al. found that the integral membrane protein synaptotagmin-3 (Syt3) is predominantly found on postsynaptic endocytic zones of neurons, where it promotes AMPA receptor internalization (see the Perspective by Mandelberg and Tsien). In Syt3 overexpressing or knockdown neurons, synaptic transmission and short-term plasticity were unchanged. However, in neurons from Syt3 knockout mice, synaptic long-term depression was abolished and decaying long-term potentiation endured. In Syt3 knockout mice, spatial learning was unaltered; however, these animals showed signs of impaired forgetting and relearning during the water maze spatial memory task. Science , this issue p. eaav1483 ; see also p. 31 In mice, the neuronal membrane trafficking protein synaptotagmin-3 is involved in learning processes that require forgetting. Forgetting is important. Without it, the relative importance of acquired memories in a changing environment is lost. We discovered that synaptotagmin-3 (Syt3) localizes to postsynaptic endocytic zones and removes AMPA receptors from synaptic plasma membranes in response to stimulation. AMPA receptor internalization, long-term depression (LTD), and decay of long-term potentiation (LTP) of synaptic strength required calcium-sensing by Syt3 and were abolished through Syt3 knockout. In spatial memory tasks, mice in which Syt3 was knocked out learned normally but exhibited a lack of forgetting. Disrupting Syt3:GluA2 binding in a wild-type background mimicked the lack of LTP decay and lack of forgetting, and these effects were occluded in the Syt3 knockout background. Our findings provide evidence for a molecular mechanism in which Syt3 internalizes AMPA receptors to depress synaptic strength and promote forgetting.

Learning and memory processes require experience-dependent changes in chromatin modifications. Here the authors provide a detailed view of the gene regulatory roles of DNA methylation and histone modifications during the acquisition and maintenance of memory across different cell types and brain regions. The ability to form memories is a prerequisite for an organism's behavioral adaptation to environmental changes. At the molecular level, the acquisition and maintenance of memory requires changes in chromatin modifications. In an effort to unravel the epigenetic network underlying both short- and long-term memory, we examined chromatin modification changes in two distinct mouse brain regions, two cell types and three time points before and after contextual learning. We found that histone modifications predominantly changed during memory acquisition and correlated surprisingly little with changes in gene expression. Although long-lasting changes were almost exclusive to neurons, learning-related histone modification and DNA methylation changes also occurred in non-neuronal cell types, suggesting a functional role for non-neuronal cells in epigenetic learning. Finally, our data provide evidence for a molecular framework of memory acquisition and maintenance, wherein DNA methylation could alter the expression and splicing of genes involved in functional plasticity and synaptic wiring.

Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.

Aberrant histone acetylation contributes to age-dependent cognitive decline and neurodegenerative diseases. We analyze the function of lysine acetyltransferase TIP60/KAT5 in neurons of the hippocampus using an inducible mouse model. TIP60-deficiency in the adult forebrain leads within days to extensive transcriptional dysfunction characterized by the presence of a neurodegeneration-related signature in CA1. Cell cycle- and immunity-related genes are upregulated while learning- and neuronal plasticity-related genes are downregulated. The dysregulated genes seen under TIP60-deficiency overlap with those in the well-characterized CK-p25 neurodegeneration model. We found that H4K12 is hypoacetylated at the transcriptional start sites of those genes whose expression is dampened in TIP60-deficient mice. Transcriptional dysregulation is followed over a period of weeks by activation of Caspase 3 and fragmentation of β-actin in CA1 neurites, eventually leading to severe neuronal loss. TIP60-deficient mice also develop mild memory impairment. These phenotypes point to a central role of TIP60 in transcriptional networks that are critical for neuronal viability.

Aging is accompanied by gradually increasing impairment of cognitive abilities and constitutes the main risk factor of neurodegenerative conditions like Alzheimer's disease (AD). The underlying mechanisms are however not well understood. Here we analyze the hippocampal transcriptome of young adult mice and two groups of mice at advanced age using RNA sequencing. This approach enabled us to test differential expression of coding and non-coding transcripts, as well as differential splicing and RNA editing. We report a specific age-associated gene expression signature that is associated with major genetic risk factors for late-onset AD (LOAD). This signature is dominated by neuroinflammatory processes, specifically activation of the complement system at the level of increased gene expression, while de-regulation of neuronal plasticity appears to be mediated by compromised RNA splicing.

Background/Objectives: Cardiovascular diseases are one of the leading causes of morbidity and mortality worldwide. Health-related quality of life is crucial to assess the impact of cardiovascular diseases and to guide therapeutic strategies. The Short Form 36 Health Survey and the RAND 36-Item Health Survey questionnaires are common tools for measuring health-related quality of life in patients with cardiovascular disease, but their reliability may vary according to the population studied. The aim of this study is to compare the reliability of the SF-36 and the RAND-36 in a population with cardiac pathology, addressing the question of which of these instruments offers a more consistent and useful measurement in this specific group. Methods: A cross-sectional observational study was carried out at the University Hospital of Burgos (Spain). A total of 413 patients with cardiovascular pathology referred to the Cardiac Rehabilitation Unit were included. Patients with incomplete data or who did not participate in the program were excluded. Internal consistency (Cronbach’s alpha), item–total correlation and reliability, and a half-and-half analysis were performed. Results: Both questionnaires showed similar and adequate reliability for patients with cardiovascular pathology. Internal consistency, as measured with Cronbach’s alpha, was above 0.80 for most dimensions, supporting its robustness. Significant inter-item and inter-dimension correlations were found in both scales, except in some specific cases in the dimension ‘Physical Functioning’. The half-and-half analysis confirmed the good reliability of both scales. Conclusions: Both the SF-36 and the RAND-36 are highly reliable tools for assessing health-related quality of life in patients with cardiovascular disease. The results may have significant implications for clinical practice, helping in the selection of health-related quality of life monitoring instruments and in the evaluation of the efficacy of therapeutic interventions.

Alzheimer's disease is a devastating neurodegenerative disease eventually leading to dementia. An effective treatment does not yet exist. Here we show that oral application of the compound anle138b restores hippocampal synaptic and transcriptional plasticity as well as spatial memory in a mouse model for Alzheimer's disease, when given orally before or after the onset of pathology. At the mechanistic level, we provide evidence that anle138b blocks the activity of conducting Aβ pores without changing the membrane embedded Aβ‐oligomer structure. In conclusion, our data suggest that anle138b is a novel and promising compound to treat AD‐related pathology that should be investigated further. Synopsis Although a substantial amount of data point to a causative role of amyloid beta and Tau pathology in Alzheimer's disease (AD) pathogenesis, no effective therapy has been developed. This study reports that anle138b blocks amyloid beta channels formation and ameliorates disease pathology. Amyloid beta peptides form conducting channels in neuronal membranes. Amyloid beta channels lead to a loss of cellular homeostasis and memory impairment. The small molecule compound anle138b blocks amyloid beta channels and ameliorates disease phenotypes in animal models. The small molecule compound anle138b also reinstates homeostasis in model of Tau‐pathology. Graphical Abstract Although a substantial amount of data point to a causative role of amyloid beta and Tau pathology in Alzheimer's disease (AD) pathogenesis, no effective therapy has been developed. This study reports that anle138b blocks amyloid beta channels formation and ameliorates disease pathology.

Activity-driven transcription is a key event associated with long-lasting forms of neuronal plasticity. Despite the efforts to investigate the regulatory mechanisms that control this complex process and the important advances in the knowledge of the function of many activity-induced genes in neurons, as well as the specific contribution of activity-regulated transcription factors, our understanding of how activity-driven transcription operates at the systems biology level is still very limited. This review focuses on the research of neuronal activity-driven transcription from an “omics” perspective. We will discuss the different high-throughput approaches undertaken to characterize the gene programs downstream of specific activity-regulated transcription factors, including CREB, SRF, MeCP2, Fos, Npas4, and others, and the interplay between epigenetic and transcriptional mechanisms underlying neuronal plasticity changes. Although basic questions remain unanswered and important challenges still lie ahead, the refinement of genome-wide techniques for investigating the neuronal transcriptome and epigenome promises great advances.