Ubiquitin-specific peptidase 18 (USP18) is an important member of the deubiquitinating enzyme family, which has received much attention in recent years for its role in microglia regulation. The aim of this study was to investigate the role of USP18 in midbrain and its potential molecular mechanisms.

In this study, we assessed behavioural phenotypes and pathological changes by adeno-associated virus (AAV)-mediated midbrain-specific USP18 high-expression mouse model. RNA sequencing and untargeted metabolomics were used for multi-omics analysis, and protein expression was detected by Western blot, and ELISA was used to detect neuroinflammatory factor levels.

Our analyses suggest that USP18 is a key regulator of immune activity in the midbrain. USP18 helps maintain the resting state of microglia and exerts neuroprotective effects by promoting TH protein expression. In the midbrain, interference with USP18 expression resulted in significant changes in neuroimmune responses, gene expression associated with inflammation, and metabolite levels. Notably, the TLR signalling pathway was significantly enriched. Loss of USP18 led to a significant increase in the expression of TLR2, Iba-1, and GFAP proteins and a significant decrease in TH levels, and this change was particularly pronounced in microglia. Importantly, the changes observed in USP18 silencing were also reflected in brain tissues of human neurodegenerative diseases.

This study reveals the critical role of USP18 in midbrain and microglia, and suggests it can finely regulate neuroinflammatory and immune responses by modulating TLR2 protein levels. The findings provide new ideas for understanding mechanisms of neurodegenerative diseases and developing therapeutic strategies.

X-ALD is a white matter (WM) disease caused by mutations in the ABCD1 gene encoding the transporter of very-long-chain fatty acids (VLCFAs) into peroxisomes. Strikingly, the same ABCD1 mutation causes either devastating brain inflammatory demyelination during childhood or, more often, progressive spinal cord axonopathy starting in middle-aged adults. The accumulation of undegraded VLCFA in glial cell membranes and myelin has long been thought to be the central mechanism of X-ALD.

This review discusses studies in mouse and drosophila models that have modified our views of X-ALD pathogenesis.

In the Abcd1 knockout (KO) mouse that mimics the spinal cord disease, the late manifestations of axonopathy are rapidly reversed by ABCD1 gene transfer into spinal cord oligodendrocytes (OLs). In a peroxin-5 KO mouse model, the selective impairment of peroxisomal biogenesis in OLs achieves an almost perfect phenocopy of cerebral ALD. A drosophila knockout model revealed that VLCFA accumulation in glial myelinating cells causes the production of a toxic lipid able to poison axons and activate inflammatory cells. Other mouse models showed the critical role of OLs in providing energy substrates to axons. In addition, studies on microglial changing substates have improved our understanding of neuroinflammation.

Animal models supporting a primary role of OLs and axonal pathology and a secondary role of microglia allow us to revisit of X-ALD mechanisms. Beyond ABCD1 mutations, pathogenesis depends on unidentified contributors, such as genetic background, cell-specific epigenomics, potential environmental triggers, and stochasticity of crosstalk between multiple cell types among billions of glial cells and neurons.

"Biological aging clocks"-composite molecular markers thought to capture an individual's biological age-have been traditionally developed through bulk-level analyses of mixed cells and tissues. However, recent evidence highlights the importance of gaining single-cell-level insights into the aging process. Microglia are key immune cells in the brain shown to adapt functionally in aging and disease. Recent studies have generated single-cell RNA-sequencing (scRNA-seq) datasets that transcriptionally profile microglia during aging and development. Leveraging such datasets in humans and mice, we develop and compare computational approaches for generating transcriptome-wide summaries from microglia to establish robust and applicable aging clocks. Our results reveal that unsupervised, frequency-based summarization approaches, which encode distributions of cells across molecular subtypes, strike a balance in accuracy, interpretability, and computational efficiency. Notably, our computationally derived microglia markers achieve strong accuracy in predicting chronological age across three diverse single-cell datasets, suggesting that microglia exhibit characteristic changes in gene expression during aging and development that can be computationally summarized to create robust markers of biological aging. We further extrapolate and demonstrate the applicability of single-cell-based microglia clocks to readily available bulk RNA-seq data with an environmental input (early life stress), indicating the potential for broad utility of our models across genomic modalities and for testing hypotheses about how environmental inputs affect brain age. Such single-cell-derived markers can yield insights into the determinants of brain aging, ultimately promoting interventions that beneficially modulate health and disease trajectories.

As research on microRNAs (miRNAs) advances, it is becoming increasingly clear that these small molecules play crucial roles in the central nervous system (CNS). They are involved in various essential neuronal functions, with specific miRNAs preferentially expressed in different cell types within the nervous system. Notably, certain miRNAs are found at higher levels in the brain and spinal cord compared to other tissues, suggesting they may have specialized functions in the CNS. miRNAs associated with long-term neurodegenerative changes could serve as valuable tools for early treatment decisions and disease monitoring. The significance of miRNAs such as miR-320, miR-146 and miR-29 in the early diagnosis of neurodegenerative disorders becomes evident, especially considering that many neurological and physical symptoms manifest only after substantial degeneration of specific neurons. Interestingly, serum miRNA levels such as miR-92 and miR-486 may correlate with various MRI parameters in multiple sclerosis. Targeting miRNAs using antisense strategies, such as antisense miR-146 and miR-485, may provide advantages over targeting mRNAs, as a single anti-miRNA can regulate multiple disease-related genes. In the future, anti-miRNA-based therapeutic approaches could be integrated into the clinical management of neurological diseases. Certain miRNAs, including miR-223, miR-106, miR-181, and miR-146, contribute to the pathogenesis of various neurodegenerative diseases and thus warrant greater attention. This knowledge could pave the way for the identification of new diagnostic, prognostic, and theranostic biomarkers, and potentially guiding the development of RNA-based therapeutic strategies. This review highlights recent research on the roles of miRNAs in the nervous system, particularly their protective functions in neurodegenerative disorders.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective therapies. It is well known that chronic neuroinflammation plays a critical role in the onset and progression of AD. Well-balanced neuronal-microglial interactions are essential for brain functions. However, determining the role of microglia-the primary immune cells in the brain-in neuroinflammation in AD and the associated molecular basis has been challenging.

Inflammatory factors in the sera of AD patients were detected and their association with microglia activation was analyzed. The mechanism for microglial inflammation was investigated. IL6 and TNF-α were found to be significantly increased in the AD stage.

Our analysis revealed that microglia were extensively activated in AD cerebra, releasing sufficient amounts of cytokines to impair the neural stem cells (NSCs) function. Moreover, the ApoD-induced NLRC4 inflammasome was activated in microglia, which gave rise to the proinflammatory phenotype. Targeting the microglial ApoD promoted NSC self-renewal and inhibited neuron apoptosis. These findings demonstrate the critical role of ApoD in microglial inflammasome activation, and for the first time reveal that microglia-induced inflammation suppresses neuronal proliferation.

Our studies establish the cellular basis for microglia activation in AD progression and shed light on cellular interactions important for AD treatment.

Microglia, the major population of brain resident macrophages, differentiate from yolk sac progenitors in the embryo and play multiple nonimmune roles in brain organization throughout development and life. Various microglia subtypes have been described by transcriptomic and proteomic signatures, involved metabolic pathways, morphology, intracellular complexity, time of residency, and ontogeny, both in development and in disease settings. Such macrophage heterogeneity increases with aging or neurodegeneration. Monocytes' infiltration and differentiation into monocyte-derived macrophages (MDMs) in the brain contribute to this diversity. Microbiota's role in brain diseases has been recently highlighted, revealing how microbial signals, such as metabolites, influence microglia and MDMs. In this brief review, we describe how these signals can influence microglia through their sensome and shape MDMs from their development in the bone marrow to their differentiation in the brain. Monocytes could then be a crucial player in the constitution of a dysbiotic gut-brain axis in neurodegenerative diseases and aging.

Growing genetic and pathological evidence has identified microglial dysfunction as a key contributor to the pathogenesis and progression of various neurological disorders, positioning microglia replacement as a promising therapeutic strategy. Traditional bone marrow transplantation (BMT) methods for replenishing brain microglia have limitations, including low efficiency and the potential for brain injury because of preconditioning regimens, such as irradiation or chemotherapy. Moreover, BM-derived cells that migrate to the brain do not recapitulate the phenotypic and functional properties of resident microglia. Here, we present a microglia transplantation strategy devoid of any conditioning, termed "tricyclic microglial depletion for transplantation" (TCMDT). This approach leverages three cycles of microglial depletion using the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX3397, creating an optimal window for efficient engraftment of exogenous microglia. Transplantation of primary cultured microglia by TCMDT successfully restored the identity and functions of endogenous microglia. To evaluate the therapeutic potential of TCMDT, we applied this strategy to two distinct mouse models of neurologic disorder. In a Sandhoff disease model, a neurodegenerative lysosomal storage disorder caused by hexosaminidase subunit beta (Hexb) deficiency, TCMDT effectively replaced deficient microglia, attenuating neurodegeneration and improving motor performance. Similarly, in an Alzheimer's disease (AD)-related amyloid mouse model carrying the triggering receptor expressed on myeloid cells 2 (Trem2) R47H mutation, our transplantation strategy rescued microglial dysfunction and mitigated AD-related pathology. Overall, our study introduces TCMDT as a practical, efficient, and safe approach for microglia replacement, suggesting therapeutic potential for treating neurological disorders associated with microglial dysfunction.

While several hypotheses have been proposed to explain the underlying mechanisms of Alzheimer's disease, none have been entirely satisfactory. Both genetic and non-genetic risk factors, such as infections, metabolic disorders and psychological stress, contribute to this debilitating disease. Multiple lines of evidence indicate that ceramides may be central to the pathogenesis of Alzheimer's disease. Tumor necrosis factor-α, saturated fatty acids and cortisol elevate the brain levels of ceramides, while genetic risk factors, such as mutations in APP, presenilin, TREM2 and APOE ε4, also elevate ceramide synthesis. Importantly, ceramides displace sphingomyelin and cholesterol from lipid raft-like membrane patches that connect the endoplasmic reticulum and mitochondria, disturbing mitochondrial oxidative phosphorylation and energy production. As a consequence, the flattening of lipid rafts alters the function of γ-secretase, leading to increased production of Aβ42. Moreover, ceramides inhibit the insulin-signaling cascade via at least three mechanisms, resulting in the activation of glycogen synthase kinase-3 β. Activation of this kinase has multiple consequences, as it further deteriorates insulin resistance, promotes the transcription of BACE1, causes hyperphosphorylation of tau and inhibits the transcription factor Nrf2. Functional Nrf2 prevents apoptosis, mediates anti-inflammatory activity and improves blood-brain barrier function. Thus, various seemingly unrelated Alzheimer's disease risk factors converge on ceramide production, whereas the elevated levels of ceramides give rise to the well-known pathological features of Alzheimer's disease. Understanding and targeting these mechanisms may provide a promising foundation for the development of novel preventive and therapeutic strategies.

Multiple sclerosis (MS) is a chronic, immune-mediated disease that affects young adults, leading to neurological disability. Regardless of the studies and the research involved in developing an efficient disease-modifying therapy (DMT), relapsing-remitting multiple sclerosis (RRMS) will transition to a progressive multiple sclerosis phenotype. The moment of transition from RRMS to secondary progressive multiple sclerosis (SPMS) is difficult to predict, and the diagnosis is based on the accumulation of disabilities in the evolution of the disease. Research on microRNAs' (miRNAs) role in MS began in the early 2000s, with miR-155 frequently cited for its link to blood-brain barrier dysfunction and neurodegeneration, making it an early transition biomarker from RRMS to SPMS. The purpose of this review is to reveal the importance of finding a biomarker from the molecular field that will be able to identify the transition phase so patients can receive high-efficacy treatments and to cease the clinical progression.

Despite the success of antiretroviral therapy (ART) in suppressing viral replication in the blood, HIV persists in the central nervous system (CNS) and causes chronic neurocognitive impairment, a hallmark of HIV-associated neurocognitive disorders (HAND). This review looks at the complex interactions among HIV, the blood-brain barrier (BBB), neuroinflammation, and the roles of viral proteins, immune cell trafficking, and pro-inflammatory mediators in establishing and maintaining latent viral reservoirs in the CNS, particularly microglia and astrocytes. Key findings show disruption of the BBB, monocyte infiltration, and activation of CNS-resident cells by HIV proteins like Tat and gp120, contributing to the neuroinflammatory environment and neuronal damage. Advances in epigenetic regulation of latency have identified targets like histone modifications and DNA methylation, and new therapeutic strategies like latency-reversing agents (LRAs), gene editing (CRISPR/Cas9), and nanoparticle-based drug delivery also offer hope. While we have made significant progress in understanding the molecular basis of HIV persistence in the CNS, overcoming the challenges of BBB penetration and neuroinflammation is key to developing effective therapies. Further research into combination therapies and novel drug delivery systems will help improve outcomes for HAND patients and bring us closer to a functional cure for HIV.

White matter injury is caused by cerebral blood flow disturbances associated with stroke and demyelinating diseases such as multiple sclerosis. Remyelination is induced spontaneously after white matter injury, but progressive multiple sclerosis and white matter stroke are usually characterised by remyelination failure. However, the mechanisms underlying impaired remyelination in lesions caused by demyelination and stroke remain unclear. In the current study, we demonstrated that collagen fibres accumulated in the demyelinated lesions of multiple sclerosis patients (age range 23-80 years) and white matter lesions of stroke patients (age range 80-87 years), suggesting that the accumulation of collagen fibres correlates with remyelination failure in these lesions. To investigate the function of collagen fibres in the white matter lesions, we generated two types of white matter injury in mice. We induced focal demyelination by lysolecithin (LPC) injection and ischemic stroke by endothelin 1 (ET1) injection into the internal capsule. We found that type I collagen fibres were secreted in ET1-induced lesions with impaired white matter regeneration in the chronic phase of disease. We also showed that monocyte-derived macrophages that infiltrated into lesions from the peripheral blood produced type I collagen after white matter injury, and that type I collagen also exacerbated microglial activation, astrogliosis, and axonal injury. Finally, we demonstrated that oligodendrocyte differentiation and remyelination were inhibited in the presence of type I collagen after LPC-induced demyelination. These results suggest that type I collagen secreted by monocyte-derived macrophages inhibited white matter regeneration, and therefore, the modulation of type I collagen metabolism might be a novel therapeutic target for white matter injury.

A new family of steroidal compounds based on a heteroaryl-4,5-dihydropyrazole thiazolinone core structure was designed and synthesized through structural modifications. The anti-neuroinflammatory activity of these compounds was evaluated in lipopolysaccharide (LPS)-stimulated murine microglial BV-2 cells in vitro. Among the synthesized compounds, 10b and 10d effectively inhibited nitric oxide (NO) production, with compound 10b emerging as the most potent anti-neuroinflammatory agent (IC50 = 2.05 μM). Compound 10b demonstrated significantly greater inhibitory effects than progesterone (prog) (IC50 = 3.23 μM) and reduced NO production in a concentration-dependent manner. Furthermore, compound 10b attenuated the release of pro-inflammatory mediators, including tumour necrosis factor (TNF)-α, interleukin-1β (IL-1β), interleukin-6 (IL-6), and prostaglandin E2 (PGE2). It also inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Mechanistic studies revealed that compound 10b significantly suppressed the transcriptional activity of nuclear factor kappa B (NF-κB) in activated microglial cells and prevented NF-κB p65 activation and IκBα degradation. These effects were likely mediated by the inhibition of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathways. Additionally, molecular docking studies suggested that the anti-neuroinflammatory effects of compound 10b may result from its hydrophobic and hydrophilic interactions with iNOS and COX-2, supporting its proposed mechanism of action. In summary, these findings suggest that compound 10b exerts anti-neuroinflammatory effects in LPS-stimulated BV-2 microglial cells by modulating key inflammatory pathways, including NF-κB and MAPK signaling.

Optimizing the design of nanoparticulate co-delivery systems of antigens and immunomodulators to induce antigen-specific immune tolerance effectively remains a challenge, constrained by low drug loading capacity and premature leakage of active ingredients. Here, we report a prodrug self-assembled nanoparticles (NPs) strategy to synergistically deliver antigen and rapamycin (RAPA) into antigen-presenting cells (APCs) by simply conjugating rapamycin with an aliphatic chain. These prodrug NPs can be efficiently taken up by APCs and then release rapamycin through cleavage of the linker by intracellular esterase. Compared to other nanocarriers, rapamycin prodrug NPs exhibit high drug loading capacity and high stability, providing more rational intracellular synchronous delivery of drugs. The prodrug NPs also demonstrate improved therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE) model mice compared with free antigen and rapamycin. Our findings provide new insights into the design of tolerogenic NPs for treating multiple sclerosis (MS). This delivery platform is also applicable for the alleviation of other autoimmune diseases.

Microglia, the brain's resident macrophages, participate in development and influence neuroinflammation, which is characteristic of multiple brain pathologies. Diverse insults cause microglia to alter their morphology from "resting" to "activated" shapes, which vary with stimulus type, brain location, and microenvironment. This morphologic diversity commonly restricts microglial analyses to specific regions and manual methods. We introduce StainAI, a deep learning tool that leverages 20x whole-slide immunohistochemistry images for rapid, high-throughput analysis of microglial morphology. StainAI maps microglia to a brain atlas, classifies their morphology, quantifies morphometric features, and computes an activation score for any region of interest. As a proof of principle, StainAI was applied to a rat model of pediatric asphyxial cardiac arrest, accurately classifying millions of microglia across multiple slices, surpassing current methods by orders of magnitude, and identifying both known and novel activation patterns. Extending its application to a non-human primate model of simian immunodeficiency virus infection further demonstrated its generalizability beyond rodent datasets, providing new insights into microglial responses across species. StainAI offers a scalable, high-throughput solution for microglial analysis from routine immunohistochemistry images, accelerating research in microglial biology and neuroinflammation.

The hypothalamus in the central nervous system (CNS) has important functions in controlling systemic metabolism. A calorie-rich diet triggers CNS immune activation, impairing metabolic control and promoting obesity and Type 2 Diabetes (T2D), but the mechanisms driving hypothalamic immune activation remain unclear. Here we identify regulatory T cells (Tregs) as key modulators of hypothalamic immune responses. In mice, calorie-rich environments activate hypothalamic CD4+ T cells, infiltrating macrophages and microglia while reducing hypothalamic Tregs. mRNA profiling of hypothalamic CD4+ T cells reveals a Th1-like activation state, with increased Tbx21, Cxcr3 and Cd226 but decreased Ccr7 and S1pr1. Importantly, results from Treg loss-of function and gain-of-function experiments show that Tregs limit hypothalamic immune activation and reverse metabolic impairments induced by hyper-caloric feeding. Our findings thus help refine the current model of Treg-centered immune-metabolic crosstalk in the brain and may contribute to the development of precision immune modulation for obesity and diabetes.

Intracerebral hemorrhage (ICH) is a serious cerebrovascular disease with high morbidity, mortality, and disability rates, largely due to neuroinflammation. Diosmetin, a natural flavonoid, has known neuroprotective effects in cerebral ischemia/reperfusion models but has been less studied in ICH. Our previous study developed diosmetin-loaded lactoferrin-modified long-circulating liposomes (Lf-Dios-Lcl), which penetrate the BBB and improve diosmetin bioavailability and brain distribution. In this study, we found that diosmetin reduced the levels of proinflammatory cytokines (IL-1β and TNF-α) and increased the level of the anti-inflammatory cytokine IL-10 in LPS-induced BV2 cells, promoting microglial polarization toward the anti-inflammatory M2 phenotype. In ICH model rats, Lf-Dios-Lcl (1 mg/kg) effectively reduced neuroinflammation, decreased IL-1β and TNF-α levels, increased IL-10 levels, and increased the proportion of CD206-positive microglia in brain tissues. Moreover, Lf-Dios-Lcl significantly downregulated p-p38 expression, suggesting that p38 signaling activation was inhibited. Overall, Lf-Dios-Lcl demonstrated brain-targeting properties and antineuroinflammatory effects by modulating microglial polarization via the p38 pathway.

This study aimed to observe the effect of electroacupuncture (EA) at Zusanli point (ST36) on motor function of cerebral ischemia mice, and to observe the effect of EA on mitochondrial morphology of peri-infarct cortex neurons in cerebral ischemia mice.

Middle cerebral artery occlusion (MCAO) was used to develop an ischemic stroke mice model. EA treatment was performed for three consecutive days for 15 min per day after MCAO modeling. We investigated the therapeutic effects of EA on MCAO mice by performing neurobehavioral assessment (modified Neurological Severity Score, Rotarod test, Open-field test and Gait analysis) and TTC staining. The morphology and function of neuronal mitochondria were evaluated by transmission electron microscopy, qRT-PCR, chemiluminescence, and western blot. Nissl staining, TUNEL staining and immunofluorescence staining were used to observe neuronal morphology and apoptosis. Furthermore, ELISA was employed to measure the expression levels of inflammatory factors in mouse serum.

EA alleviated motor dysfunction and infarct volume in mice with cerebral ischemia. It improved the neuronal mitochondria damage in MCAO mice, and decreased the protein and mRNA expression level of mitochondrial fission related proteins (FIS1 and Drp1). In addition, EA can reduce neuronal damage and apoptosis of nerve cells, and decrease the level of inflammatory factors (IL-1β, TNF-α, IL-6 and IL-8) in cerebral ischemia mice.

EA therapy can improve motor dysfunction and alleviate the damage of neuron mitochondria in cerebral ischemic mice.

The immune system is crucial for the correct brain development, and recent findings also point toward central control of immune response. As the immune system is not fully developed at birth, the early years become an important window for infections and for the development of epilepsy. Both central and even peripheral inflammation may impact brain function, promoting opening of the blood-brain/blood and cerebrospinal barriers and allowing entry of immune cells and cytokines, which in turn may affect neuron function and connections. The resident brain immune cells, microglia, besides providing protection, also affect neurons, myelination, and astrocyte function. They may, via the complement system, remove synapses, both physiologically and pathologically. After seizures during development, activated microglia releases proinflammatory molecules, which are detrimental for neurons, and inhibition of microglial activation shows promising antiepileptogenic effects. In addition to cytokines, seizures and excessive excitability stimulate calpain 2 expression, which can promote neuron loss and contribute to amplification of inflammatory responses via stimulation of proinflammatory cytokines. In summary, the immature immune system during postnatal early life may be an important target for the development of long-desired antiepileptogenic drugs.

Motor coordination relies on muscle spindles and the stretch reflexes they enable. A new study shows that spindle-resident macrophages can drive sensory signaling and muscle contraction. This implicates immune cells in a process considered the exclusive domain of neuromuscular systems.

Delirium is a common acute onset neurological syndrome characterised by transient fluctuations in cognition. It affects over 20% of medical inpatients and 50% of those critically ill. Delirium is associated with morbidity and mortality, causes distress to patients and carers, and has significant socioeconomic costs in ageing populations. Despite its clinical significance, the pathophysiology of delirium is understudied, and many underlying cellular mechanisms remain unknown. There are currently no effective pharmacological treatments which directly target underlying disease processes. Although many studies focus on neuronal dysfunction in delirium, glial cells, primarily astrocytes, microglia, and oligodendrocytes, and their associated systems, are increasingly implicated in delirium pathophysiology. In this review, we discuss current evidence which implicates glial cells in delirium, including biomarker studies, post-mortem tissue analyses and pre-clinical models. In particular, we focus on how astrocyte pathology, including aberrant brain energy metabolism and glymphatic dysfunction, reactive microglia, blood-brain barrier impairment, and white matter changes may contribute to the pathogenesis of delirium. We also outline limitations in this body of work and the unique challenges faced in identifying causative mechanisms in delirium. Finally, we discuss how established neuroimaging and single-cell techniques may provide further mechanistic insight at pre-clinical and clinical levels.

Multiple sclerosis (MS) manifests as progressive disability stemming from the demyelination of axons within the central nervous system, resulting in neuronal loss and atrophy in the brain and spinal cord. Diagnosis typically entails a thorough assessment of medical history, symptoms, physical examination, and various diagnostic procedures, including magnetic resonance imaging, cerebrospinal fluid analysis, blood tests, and electrophysiology. However, existing biomarkers often fail to reliably correlate with disease progression. Understanding the molecular mechanisms driving disease progression, particularly the transition from relapsing-remitting MS (RRMS), marked by inflammation, to secondary progressive MS (SPMS), characterized by neurodegeneration, remains a formidable challenge for healthcare providers. Despite extensive research efforts, dependable markers indicating disease stage and activity remain elusive. Circulating microRNAs (miRNAs) have emerged as promising candidates for both MS diagnosis and prognosis due to their altered expression patterns across the disease spectrum. Differential expression of miRNA panels between RRMS and SPMS holds the potential to offer valuable insights into disease progression and to inform treatment strategies aimed at halting disability advancement. This review seeks to delve into current research exploring the differences in miRNA panel expression across various phases of MS.

Microglia are exceptionally dynamic resident innate immune cells within the central nervous system, existing on a continuum of morphologies and functions throughout their lifespan. They play vital roles in response to injuries and infections, clearing cellular debris, and maintaining neural homeostasis throughout development. Emerging research suggests that microglia are strongly influenced by biological factors, including sex, developmental stage, and their local environment. This review synthesizes findings on sex differences in microglial morphology and function in key brain regions, including the frontal cortex, hippocampus, amygdala, hypothalamus, basal ganglia, and cerebellum, across the lifespan. Where available, we examine how gonadal hormones influence these microglial characteristics. Additionally, we highlight the limitations of relying solely on morphology to infer function and underscore the need for comprehensive, multimodal approaches to guide future research. Ultimately, this review aims to advance the dialogue on these spatiotemporally heterogeneous cells and their implications for sex differences in brain function and vulnerability to neurological and psychiatric disorders.

Adolescence is a crucial period marked by profound changes in the brain. Exposure to psychological stressors such as bullying, abuse or maltreatment during this developmental period may increase the risk of developing depression, anxiety and comorbid cardiometabolic conditions. Chronic psychological stress is associated with behavioral changes and disruption of the hypothalamic-pituitary-adrenal axis, leading to corticosterone overproduction in rodents and changes in both the immune system and the gut microbiome. Here, we demonstrate the ability of Bifidobacterium longum CECT 30763 (B. longum) to ameliorate adolescent depressive and anxiety-like behaviors in a chronic social defeat (CSD) mouse model. The mechanisms underlying this beneficial effect are related to the ability of B. longum to attenuate the inflammation and immune cell changes induced by CSD after the initial stress exposure through the induction of T regulatory cells with enduring effects that may prevent and mitigate the adverse consequences of repeated stress exposure on mental and cardiometabolic health. B. longum administration also normalized dopamine release, metabolism and signaling at the end of the intervention, which may secondarily contribute to the reversal of behavioral changes. The anti-inflammatory effects of B. longum could also explain its cardioprotective effects, which were reflected in an amelioration of the oxidative stress-induced damage in the heart and improved lipid metabolism in the liver. Overall, our findings suggest that B. longum regulates the links between the immune and dopaminergic systems from the gut to the brain, potentially underpinning its beneficial psychobiotic and physiological effects in CSD.

Microglia-resident immune cells in the central nervous system-undergo morphological and functional changes in response to signals from the local environment and mature into various homeostatic states. However, niche signals underlying microglial differentiation and maturation remain unknown. Here, we show that neuronal micronuclei (MN) transfer to microglia, which is followed by changing microglial characteristics during the postnatal period. Neurons passing through a dense region of the developing neocortex give rise to MN and release them into the extracellular space, before being incorporated into microglia and inducing morphological changes. Two-photon imaging analyses have revealed that microglia incorporating MN tend to slowly retract their processes. Loss of the cGAS gene alleviates effects on micronucleus-dependent morphological changes. Neuronal MN-harboring microglia also exhibit unique transcriptome signatures. These results demonstrate that neuronal MN serve as niche signals that transform microglia, and provide a potential mechanism for regulation of microglial characteristics in the early postnatal neocortex.

Maintenance of the retina, part of the central nervous system, and other structures in the eye is critical for vision preservation. Aging increases the prevalence of vision impairment, including glaucoma, macular degeneration, and diabetic retinopathy. The retina is primarily maintained by glial cells; however, recent literature suggests that lymphocytes may play a role in the homeostasis of central nervous system tissues. Natural antibodies are produced by B cells without infection or immunization and maintain tissue homeostasis. Here, we explored the potential role of natural immunoglobulin M (IgM) produced by B lymphocytes in maintaining retinal health during aging in mice.

Our results indicate that the vitreous humor of both mice and humans contains IgM and IgG, suggesting that these immunoglobulins may play a role in ocular function. Furthermore, we observed that aged mice lacking secreted IgM (µs-/-) exhibited pronounced retinal degeneration, accompanied by reactive gliosis, and a proinflammatory cytokine environment. This contrasts with the aged wild-type counterparts, which retain their ability to secrete IgM and maintain a better retinal structure and anti-inflammatory environment. In addition to these findings, the absence of secreted IgM was associated with significant alterations in the retinal pigment epithelium, including disruptions to its morphology and signs of increased stress. This was further observed in changes to the blood-retinal-barrier, which is critical for regulation of retinal homeostasis.

These data suggest a previously unrecognized association between a lack of secreted IgM and alterations in the retinal microenvironment, leading to enhanced retinal degeneration during aging. Although the precise mechanism remains unclear, these findings highlight the potential importance of secreted IgM in processes that support retinal health over time. By increasing our understanding of ocular aging, these results show that there is a broader role for the immune system in retinal function and integrity in advanced age, opening new areas for the exploration of immune-related interventions in age-associated retinal conditions.

The blood-brain barrier (BBB) is a critical structure that maintains brain homeostasis by selectively regulating nutrient influx and waste efflux. Not surprisingly, it is often compromised in neurodegenerative diseases. In addition to its involvement in these pathologies, the BBB also represents a significant challenge for drug delivery into the central nervous system. Nanoparticles (NPs) have been widely explored as drug carriers capable of overcoming this barrier and effectively transporting therapies to the brain. However, their potential to directly address and ameliorate BBB dysfunction has received limited attention. In this review, we examine how NPs enhance drug delivery across the BBB to treat neurodegenerative diseases and explore emerging strategies to restore the integrity of this vital structure.

Microglia are key immune cells in the central nervous system (CNS) and maintain hemostasis in physiological conditions. Microglial depletion leads to rapid repopulation, but the gene expression and signaling pathways related to repopulation remain unclear. Here, we used RNA sequencing (RNA-Seq) analysis to profile the transcriptome of microglia-depleted tissue by taking advantage of a conditional genetic microglial depletion model (CX3CR1CreER/+ system). Differential gene expression (DGE) sequencing analysis showed that 1226 genes were differentially up- and downregulated in both groups compared to control. Our data demonstrated that many microglial genes were highly regulated on day 3 after depletion but the numbers of differentially expressed genes were reduced by day 7. Gene ontology (GO) analysis categorized these differentially expressed genes on day 3 and day 7 to the specific biological processes, such as cell proliferation, cell activation, and cytokine and chemokine production. DGE analysis indicated that specific genes related to proliferation were regulated after depletion. Consistent with the changes in transcriptome, the histological analysis of transgenic mice revealed that the microglia after depletion undergo proliferation and activation from day 3 to day 7. Collectively, these results suggest that transcriptomic changes in microglial genes during depletion have a profound implication for the renewal and activation of microglia and may help to understand the regulatory mechanism of microglial activation in disease conditions.

Neural-electronic interfaces through delivering electroceuticals to lesions and modulating pathological endogenous electrical environments offer exciting opportunities to treat drug-refractory neurological disorders. Such an interface should ideally be compatible with the neural tissue and aggressive biofluid environment. Unfortunately, no interface specifically designed for the biofluid environments is available so far; instead, simply stacking an encapsulation layer on silicon-based substrates makes them susceptible to biofluid leakage, device malfunction, and foreign-body reactions. Here, we developed a biofluid-permeable and erosion-resistant wireless neural-electronic interface (BNEI) that is composed of a flexible 3D interconnected poly(l-lactide) fibrous network with a dense and axially aligned piezoelectrical molecular chain arrangement architecture. The organized molecular chain structure enhances the tortuous pathway and longitudinal piezoelectric coefficient of poly(l-lactide) fibers, improves their water barrier properties, and enables efficient conversion of low-intensity acoustic vibrations transmitted in biofluids into electrical signals, achieving long-term stable and wireless neuromodulation. A 3-month clinical trial demonstrated that the BNEI can effectively accelerate the pathological cascade in peripheral neuropathy for nerve regeneration and transcranially modulate cerebellar-cerebral circuit dynamics, suppressing seizures in temporal lobe epilepsy. The BNEI can be a clinically scalable approach for wireless neuromodulation that is broadly applicable to the modulation of neurohomeostasis in both the peripheral and central nervous systems.

Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative lysosomal storage disorders characterized by excessive accumulation of lysosomal lipofuscin. Thirteen subtypes of NCL have been identified, each associated with distinct genes encoding various transmembrane proteins, secretory proteins, or lysosomal enzymes. Clinically, NCL manifests in infants through vision impairment, motor and cognitive dysfunctions, epilepsy, and premature death. The pathological complexity of NCL has hindered the development of effective clinical protocols. Current treatment modalities, including enzyme replacement therapy, pharmacological approaches, gene therapy, and stem cell therapy, have demonstrated limited efficacy. However, emerging evidence suggests a significant relationship between NCL and microglial cells, highlighting the potential of novel microglial cell replacement therapies. This review comprehensively examines the pathogenic genes associated with various NCL subtypes, elucidating their roles, clinical presentations, and corresponding mouse models. Especially, we thoroughly discuss the advances in the clinical study of potential therapeutics, which crucially calls for early diagnosis and treatment more than ever.

Vascular calcification (VC) is a crucial risk factor for the high morbidity and mortality associated with cardiovascular and cerebrovascular diseases. With the global population aging, the incidence of VC is escalating annually. However, due to its silent clinical process, VC often results in irreversible clinical outcomes. Inflammation is a core element in the VC process, and macrophages are the major inflammatory cells. Due to their diverse origins, microenvironments, and polarization states, macrophages exhibit significant heterogeneity, exerting strong effects on the occurrence, development, and even the regression of VC. In this review, we summarize the origin, distribution, classification, and surface markers of macrophages. Simultaneously, we explore the mechanisms by which macrophages maintain homeostasis or regulate inflammation, including the macrophage-mediated regulation of VC through the release of inflammatory factors, osteogenic genes, extracellular vesicles, and alterations in efferocytosis. Finally, we discuss research targeting inflammation and macrophages to develop novel therapeutic regimens for preventing and treating VC.

Microglia, the resident innate immune cells of the central nervous system (CNS), play an important role in neuroimmune signaling, neuroprotection, and neuroinflammation. In the healthy CNS, microglia adopt a surveillant and antiinflammatory phenotype characterized by a ramified scanning morphology that maintains CNS homeostasis. In response to acquired insults, such as traumatic brain injury (TBI) or spinal cord injury (SCI), microglia undergo a dramatic morphologic and functional switch to that of a reactive state. This microglial switch is initially protective and supports the return of the injured tissue to a physiologic homeostatic state. However, there is now a significant body of evidence that both TBI and SCI can result in a chronic state of microglial activation, which contributes to neurodegeneration and impairments in long-term neurologic outcomes in humans and animal models. In this review, we discuss the complex role of microglia in the pathophysiology of TBI and SCI, and recent advancements in knowledge of microglial phenotypic states in the injured CNS. Furthermore, we highlight novel therapeutic strategies targeting chronic microglial responses in experimental models and discuss how they may ultimately be translated to the clinic for human brain and SCI.

This study aims to investigate the longitudinal changes in translocator protein (TSPO) following stroke in different brain regions and potential associations with chronic brain infarction.

Twelve patients underwent SPECT using the TSPO tracer 6-Chloro-2-(4'-123I-Iodophenyl)-3-(N,N-Diethyl)-Imidazo[1,2-a]Pyridine-3-Acetamide, as well as structural MRI, at 10, 41, and 128 days (median) after ischemic infarction in the middle cerebral artery. TSPO expression was measured in lesional (MRI lesion and SPECT lesion), connected (pons and ipsilesional thalamus), and nonconnected (ipsilesional cerebellum and contralesional occipital cortex) regions. Correlations were explored between the volume of chronic infarction and TSPO expression in nonconnected regions of interest (ROIs) at 128 days RESULTS: Throughout the study period, TSPO levels decreased by 24%-33% in lesional ROIs, while levels increased in connected ROIs by 35%-69% and in nonconnected ROIs by 53%-77%. At 128 days poststroke, TSPO expression in ipsilesional cerebellum positively correlated with chronic infarction volume (p = 0.002, r2 = 0.72).

This study expands the current knowledge of spatial and temporal TSPO expression in humans by quantifying TSPO changes in lesional, connected, and nonconnected brain regions at three time points after cerebral infarction as well as correlating late-stage TSPO upregulation and chronic infarction volume.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease mainly characterized by the accumulation of ubiquitinated proteins in the affected motor neurons. At present, the accurate pathogenesis of ALS remains unclear and there are still no effective treatment measures for ALS. The potential pathogenesis of ALS mainly includes the misfolding of some pathogenic proteins, the genetic variation, mitochondrial dysfunction, autophagy disorders, neuroinflammation, the misregulation of RNA, the altered axonal transport, and gut microbial dysbiosis. Exploring the pathogenesis of ALS is a critical step in searching for the effective therapeutic approaches. The current studies suggested that the genetic variation, gut microbial dysbiosis, the activation of glial cells, and the transportation disorder of extracellular vesicles may play some important roles in the pathogenesis of ALS. This review conducts a systematic review of these current potential promising topics closely related to the pathogenesis of ALS; it aims to provide some new evidences and clues for searching the novel treatment measures of ALS.

Although notable progress has been made, restoring motor function from the brain to the muscles continues to be a substantial clinical challenge in motor neuron diseases/disorders such as spinal cord injury (SCI). While cell transplantation has been widely explored as a potential therapeutic method for reconstructing functional motor pathways, there remains considerable opportunity for enhancing its therapeutic effectiveness. We reviewed studies on motor pathway regeneration to identify molecular and ultrastructural cues that could enhance the efficacy of cell transplantation. While the glial scar is often cited as an intractable barrier to axon regeneration, this mainly applies to axons trying to penetrate its "core" to reach the opposite side. However, the glial scar exhibits a "duality," with an anti-regenerative core and a pro-regenerative "surface." This surface permissiveness is attributed to pro-regenerative molecules, such as laminin in the basement membrane (BM). Transplanting donor cells onto the BM, which forms plastically after injury, may significantly enhance the efficacy of cell transplantation. Specifically, forming detour pathways between transplanted cells and endogenous propriospinal neurons on the pro-regenerative BM may efficiently bypass the intractable scar core and promote motor pathway regeneration. We believe harnessing the tissue's innate repair capacity is crucial, and targeting post-injury plasticity in astrocytes and Schwann cells, especially those associated with the BM that has predominantly been overlooked in the field of SCI research, can advance motor system restoration to a new stage. A shift in cell delivery routes-from the traditional intra-parenchymal (InP) route to the transplantation of donor cells onto the pro-regenerative BM via the extra-parenchymal (ExP) route-may signify a transformative step forward in neuro-regeneration research. Practically, however, the complementary use of both InP and ExP methods may offer the most substantial benefit for restoring motor pathways. We aim for this review to deepen the understanding of cell transplantation and provide a framework for evaluating the efficacy of this therapeutic modality in comparison to others.

An increasing body of evidence suggests neuroinflammation has a prominent role in the pathogenesis of Alzheimer's disease (AD). The amyloid-β-tau-neurodegeneration (ATN) classification system is now being expanded toward an amyloid-β-tau neurodegeneration-neuroinflammation (ATN(I)) system. Activated microglia and reactive astrocytes are the key hubs for neuroinflammation in AD, and chemokines are recognized as pivotal modulators of microglial innate immune functions. In this review, based on the chemokine-microglia regulatory axis, we elucidate the mechanisms through which chemokines influence microglial function, potentially modulating neurotoxicity or neuroprotection in AD. The key chemokines that significantly affect microglial polarization, such as CCL2, CCL3, and CXCL1, are summarized, and their role in disease progression are elaborated. Additionally, we explore prospective therapeutic interventions centered on the chemokine-microglia regulatory axis, offering valuable perspectives on pathobiology of AD and avenues for pharmacological advancements.

Age and insulin-like growth factor-1 (IGF-1) have an inverse association with cognitive decline and dementia. IGF-1 is known to have important pleiotropic functions beginning in neurodevelopment and extending into adulthood such as neurogenesis. At the cellular level, IGF-1 has pleiotropic signaling mechanisms through the IGF-1 receptor on neurons and neuroglia to attenuate inflammation, promote myelination, maintain astrocytic functions for homeostatic balances, and neuronal synaptogenesis. In preclinical rodent models of aging and transgenic models of IGF-1, increased IGF-1 improves cognition in a variety of behavioral paradigms along with reducing IGF-1 via knockout models being able to induce cognitive impairment. At the clinical levels, most studies highlight that increased levels of IGF-1 are associated with better cognition. This review provides a comprehensive and up-to-date evaluation of the association between IGF-1 and cognition at the cellular signaling levels, preclinical, and clinical levels.

In acute neuroinflammation, microglia activate transiently, and return to a resting state later on. However, they may retain immune memory of such event, namely priming. Primed microglia are more sensitive to new stimuli and develop exacerbated responses, representing a risk factor for neurological disorders with an inflammatory component. Strategies to control the hyperactivation of microglia are, hence, of great interest. The receptor for colony stimulating factor 1 (CSF1R), expressed in myeloid cells, is essential for microglia viability, so its blockade with specific inhibitors (e.g. PLX5622) results in significant depletion of microglial population. Interestingly, upon inhibitor withdrawal, new naïve microglia repopulate the brain. Depletion-repopulation has been proposed as a strategy to reprogram microglia. However, substantial elimination of microglia is inadvisable in human therapy. To overcome such drawback, we aimed to reprogram long-term primed microglia by CSF1R partial inhibition. Microglial priming was induced in mice by acute neuroinflammation, provoked by intracerebroventricular injection of neuraminidase. After 3-weeks recovery, low-dose PLX5622 treatment was administrated for 12 days, followed by a withdrawal period of 7 weeks. Twelve hours before euthanasia, mice received a peripheral lipopolysaccharide (LPS) immune challenge, and the subsequent microglial inflammatory response was evaluated. PLX5622 provoked a 40%-50% decrease in microglial population, but basal levels were restored 7 weeks later. In the brain regions studied, hippocampus and hypothalamus, LPS induced enhanced microgliosis and inflammatory activation in neuraminidase-injected mice, while PLX5622 treatment prevented these changes. Our results suggest that PLX5622 used at low doses reverts microglial priming and, remarkably, prevents broad microglial depletion.