Search Results (18,347)

CD44, a structurally diverse cell-surface glycoprotein, plays a multifaceted and indispensable role in neural tissue across both physiological and pathological conditions. It orchestrates complex cell–extracellular matrix interactions and intracellular signaling through its variant isoforms and post-translational modifications and is broadly expressed in neural stem/progenitor cells, microglia, astrocytes, and selected neuronal populations. The interactions of CD44 with ligands such as hyaluronan and osteopontin regulate critical cellular functions, including migration, differentiation, inflammation, and synaptic plasticity. In microglia and macrophages, CD44 mediates immune signaling and phagocytic activity, and it is dynamically upregulated in neuroinflammatory diseases, particularly through pathways involving Toll-like receptor 4. CD44 expression in astrocytes is abundant during central nervous system development and in diseases, contributing to glial differentiation, reactive astrogliosis, and scar formation. Though its expression is less prominent in mature neurons, CD44 supports neural plasticity, circuit organization, and injury-induced repair mechanisms. Additionally, its expression at nervous system barriers, such as the blood–brain barrier, underscores its role in regulating vascular permeability during inflammation and ischemia. Collectively, CD44 emerges as a critical integrator of neural cell function and intercellular communication. Although the roles of CD44 in glial cells appear to be similar to those explored in other tissues, the expression of this molecule and its variants on neurons reveals peculiar functions. Elucidating the cell-type-specific roles and regulation of CD44 variants may offer novel therapeutic strategies for diverse neurological disorders. Full article

α-Cyclodextrin/Moringin (α-CD/MOR) is an isothiocyanate showing neuroprotective and antioxidant properties. In this work, we studied in differentiated NSC-34 motor neurons cell line the molecular pathways activated following a treatment of 96 h with α-CD/MOR at different doses, namely 0.5, 5 and 10 μM. Taking advantage of comparative transcriptomic analysis, we retrieved the differentially expressed genes (DEGs) and we mapped DEGs to synaptic genes using the SynGO database. Then, we focused on the biological pathways in which they are involved. We observed that the prolonged treatment with α-CD/MOR significantly modulated biological processes and cellular components associated with synaptic organization. Interestingly, the KEGG pathway “Regulation of actin cytoskeleton” was overrepresented, alongside pathways related to synapses and axon guidance. Specifically, SPIA analysis indicated that the “Regulation of actin cytoskeleton” pathway was found to be activated with the highest dose of α-CD/MOR. Moreover, α-CD/MOR also modulated transcription factors involved in synaptic plasticity, such as Creb1. These results could indicate that α-CD/MOR can influence synaptic functions and organization, being involved in synaptic plasticity through the modulation of actin dynamics. Full article

Alzheimer’s disease (AD) and major depressive disorder (MDD) are prevalent central nervous system (CNS) disorders that share overlapping symptoms but differ in underlying molecular mechanisms. Distinguishing these mechanisms is essential for developing targeted diagnostic and therapeutic strategies. In this study, we integrated multi-tissue transcriptomic datasets from brain and peripheral samples to identify differentially expressed microRNAs (miRNAs) in AD and MDD. Functional enrichment analyses (KEGG, GO) revealed that dysregulated miRNAs in AD were associated with MAPK, PI3K–Akt, Ras, and PD-1/PD-L1 signaling, pathways linked to synaptic plasticity, neuroinflammation, and immune regulation. In contrast, MDD-associated miRNAs showed enrichment in Hippo signaling and ubiquitin-mediated proteolysis, implicating altered neurogenesis and protein homeostasis. Network analysis highlighted key disease- and tissue-specific miRNAs, notably hsa-miR-1202 and hsa-miR-24-3p, with potential roles in neuronal survival and molecular network regulation. These findings suggest that miRNAs may serve as non-invasive biomarkers for diagnosis, prognosis, and treatment monitoring in both disorders. While therapeutic targeting of miRNAs offers promise, challenges such as blood–brain barrier penetration and tissue-specific delivery remain. This integrative approach provides a translational framework for advancing miRNA-based strategies in CNS disease research. Full article

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, and key pathways such as neuroinflammation, oxidative stress, and autophagy are believed to significantly contribute to the mechanisms of neurodegeneration. Calpain activation plays a critical role in neuroinflammation and neurodegeneration, as demonstrated by its impact on microglial activation, reactive oxygen species (ROS) production, and neuronal survival. In this study, we investigated the effects of calpain inhibition using calpeptin (CP) and calpain-2-specific inhibitors in cellular and murine models of neuroinflammation and PD. In BV2 microglial cells, LPS-induced production of pro-inflammatory cytokines (TNF-α, IL-6) and chemokines (MCP-1, IP-10) were significantly reduced by CP treatment with a concomitant decrease in ROS generation. Similarly, in VSC-4.1 motoneuron cells, calpain inhibition attenuated IFN-γ-induced ROS production and improved cell viability, demonstrating its neuroprotective effects. Moreover, in a murine MPTP model of PD, calpain inhibition reduced astrogliosis, ROCK2 expression, and levels of inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-7, and IL12p70) and chemokines (MCP-1 and IP-10) in the dorsal striatum and plasma. The specific role of calpain-2 in immune modulation was further highlighted in human microglia, SV-40 cells. With respect to immune modulation in these cells, siRNA-mediated knockdown of calpain-2, but not calpain-1, significantly reduced antigen presentation to CD4+ T cells. Thus, calpain-2 is likely involved in regulating antigen presentation and activation of inflammatory CD4+ T cells. These findings underscore the therapeutic potential of calpain-2 inhibition in mitigating neuroinflammation and neurodegeneration, particularly in PD, by targeting microglial activation, ROS production, and neuronal survival pathways. Full article

Sulforaphane (SFN) is a bioactive compound belonging to the isothiocyanate family, known for its neuroprotective properties. While transcriptomic studies have highlighted SFN’s role in regulating gene expression, its impact on alternative splicing (AS), a key regulatory mechanism in neuronal metabolism, remains underexplored. In this study, we investigated whether SFN pre-treatment influences mRNA splicing patterns in an in vitro neuronal model using retinoic acid (RA)-differentiated SH-SY5Y cells. Using a dedicated RNA-seq-based splicing analysis pipeline, we identified 194 differential alternative splicing events (DASEs) associated with SFN treatment. Gene Ontology enrichment revealed significant over-representation of DNA repair processes. To better understand the functional implications, we integrated in silico predictions of premature stop codons, DASE/miRNA hybridizations, and DASE/RNA-binding protein (RBP) motif occurrences. Our findings suggest that SFN may modulate splicing of key DNA repair genes, contributing to protecting neurons against DNA damage. These preliminary results underscore a novel layer of SFN’s molecular effects and propose it as a valuable adjuvant in physiological conditions to enhance cellular health. Further studies are warranted to dissect the mechanistic underpinnings of SFN-mediated AS and its relevance in DNA-damage-related disorders. Full article

Tissue engineering has the potential to overcome the limitations of using autografts in nerve gap repair, using cellular biomaterials to bridge the gap and support neuronal regeneration. Various types of therapeutic cells could be considered for use in aligned collagen-based engineered neural tissue (EngNT), including Schwann cells and their precursors, which can be derived from human induced pluripotent stem cells (hiPSCs). Using Schwann cell precursors may have practical advantages over mature Schwann cells as they expand readily in vitro and involve a shorter differentiation period. However, the performance of each cell type needs to be tested in EngNT. By adapting established protocols, hiPSCs were differentiated into Schwann cell precursors and Schwann cells, with distinctive molecular profiles confirmed using immunocytochemistry and RT-qPCR. For the first time, both cell types were incorporated into EngNT using gel aspiration–ejection, a technique used to align and simultaneously stabilise the cellular hydrogels. Both types of cellular constructs supported and guided aligned neurite outgrowth from adult rat dorsal root ganglion neurons in vitro. Initial experiments in a rat model of nerve gap injury demonstrated the extent to which the engrafted cells survived after 2 weeks and indicated that both types of hiPSC-derived cells supported the infiltration of host neurons, Schwann cells and endothelial cells. In summary, we show that human Schwann cell precursors promote infiltrating endogenous axons in a model of peripheral nerve injury to a greater degree than their terminally differentiated Schwann cell counterparts. Full article

Microglia and macrophages are critical immune cells within the central nervous system (CNS), with distinct roles in development, homeostasis, and disease. Once viewed as passive bystanders, these cells are now recognized for their dynamic phenotypic plasticity, which enables them to respond to a wide range of physiological and pathological stimuli. During homeostasis, microglia and CNS-resident macrophages actively participate in synaptic pruning, neuronal support, myelin regulation, and immune surveillance, contributing to CNS integrity. However, under pathological conditions, these cells can adopt neurotoxic phenotypes, exacerbating neuroinflammation, oxidative stress, and neuronal damage in diseases such as Alzheimer’s, Parkinson’s, multiple sclerosis, and glioblastoma. This review synthesizes emerging insights into the molecular, epigenetic, and metabolic mechanisms that govern the behavior of microglia and macrophages, highlighting their developmental origins, niche-specific programming, and interactions with other CNS cells. We also explore novel therapeutic strategies aimed at modulating these immune cells to restore CNS homeostasis, including nanotechnology-based approaches for selective targeting, reprogramming, and imaging. Understanding the complex roles of microglia and macrophages in both health and disease is crucial for the development of precise therapies targeting neuroimmune interfaces. Continued advances in single-cell technologies and nanomedicine are paving the way for future therapeutic interventions in neurological disorders. Full article

Neospora caninum, as well as Toxoplasma gondii, secrete proteins that facilitate the invasion of host cells and the regulation of host immune response and metabolism. However, the localization of the secretory proteins in infected animal brains has not been studied in detail. Here, we investigate the brain and intracellular distribution of the secretory proteins in experimentally infected mice and naturally infected calves through histopathology and immunohistochemistry (IHC) to detect surface antigen 1 (NcSAG1), cyclophilin (NcCYP), profilin (NcPF), dense granule protein 6 (NcGRA6), and NcGRA7. These methods revealed that numerous tachyzoites positive for NcSAG1, NcCYP, NcPF, NcGRA6, and NcGRA7 were localized in and around the animals’ necrotic lesions, and NcGRA7 was diffusely observed in the necrotic lesions of the infected mice. Moreover, IHC revealed that NcGRA6 and NcGRA7 were distributed in the cytoplasm of infected neurons around the parasites in the infected mice and calves. This suggests that NcGRA6 and NcGRA7 might be directly related to the alteration of neuronal metabolism and activity, and that NcGRA7 might be related to the formation of necrotic lesions. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying efficacy. Addressing this critical therapeutic gap, natural multi-target compounds like mulberroside A (MsA)—a bioactive glycoside from Morus alba L.—present promising alternatives. This study investigated MsA’s neuroprotective potential using scopolamine-induced AD-like mice and N2a/APP695swe cells. In vivo, MsA significantly ameliorated cognitive deficits and neuronal loss, concurrently enhancing cholinergic neurotransmission through increased acetylcholine levels and inhibited acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) activities. MsA also upregulated neurotrophic factors (BDNF, CREB) in critical brain regions. In vitro, MsA restored cholinergic function, mitigated oxidative stress, and crucially reduced amyloid-β (Aβ) production by dual regulation of APP processing: promoting the non-amyloidogenic pathway via ADAM10 upregulation and inhibiting the amyloidogenic pathway via suppression of BACE1 and γ-secretase components. Mechanistically, these multi-target benefits were mediated by MsA’s activation of the PI3K/AKT pathway, which triggered downstream inhibitory phosphorylation of GSK3β—directly reduced tau hyperphosphorylation—and activation of CREB/BDNF signaling. Collectively, our findings demonstrate that MsA confers comprehensive neuroprotection against AD pathology by simultaneously targeting cholinergic dysfunction, oxidative stress, Aβ accumulation, tau phosphorylation, and impaired neurotrophic signaling, highlighting its strong therapeutic candidacy. Full article

Intercellular communication in the central nervous system (CNS) is essential for maintaining neural function and coordinating responses to injury or disease. With recent advances in single-cell and spatial transcriptomics, a growing body of research has revealed that this communication is highly dynamic, shifting across states of health, aging, demyelination, and neurodegeneration. In this review, we synthesize the current findings on intercellular communication networks involving neurons, astrocytes, microglia, oligodendrocytes, and other glial populations in the CNS across four major states: healthy homeostasis, aging, demyelinating diseases, and Alzheimer’s disease (AD). We focus on how changes in intercellular communication contribute to the maintenance or disruption of CNS integrity and function. Mechanistic insights into these signaling networks have revealed new molecular targets and pathways that may be exploited for therapeutic intervention. By comparing the intercellular signaling mechanisms across different disease contexts, we underscore the importance of CNS crosstalk not only as a hallmark of disease progression, but also as a potential gateway for precision therapy. Full article

Although the calcium-dependent proteases, calpains, were discovered more than 60 years ago, we still know very little regarding their functions, mostly because very few studies are addressing questions related to specific members of this relatively large family of cysteine proteases. The “classical calpains”, calpain-1 and calpain-2, are ubiquitous and have received more attention because of the special roles they play in the brain. The authors have been studying the properties and functions of these two calpain isoforms in the brain for over 45 years, and this review will focus on what has been learned over this period of time. In particular, we will discuss the numerous studies that have led to the notion that calpain-1 and calpain-2 play opposite functions in the brain on processes ranging from neuronal survival or death, synaptic plasticity, and learning and memory to neurogenesis. Mechanisms underlying these opposite functions are starting to be understood and the findings support the notion that such opposite functions might be a general feature of these two isoforms in any type of cell. This review concludes with a discussion of the potential benefits of selective calpain-2 inhibitors for the treatment of a variety of neurological disorders. Full article

Activated protein C (APC) exerts anticoagulant and cytoprotective cell signaling activities. APC’s cell signaling requires protease-activated receptor (PAR) PAR1 and PAR3, and APC’s PAR cleavages generate peptides capable of agonizing biased G-protein coupled receptor (GPCR) cytoprotective signaling, resulting in anti-inflammatory and anti-apoptotic activities and endothelial barrier stabilization. The PAR-sequence-derived 34-residue “G10 peptide” comprising PAR1 residues 47–55 covalently attached by a 10-glycine linker to PAR3 residues 51–65 is an orthosteric/allosteric bivalent GPCR agonist that potently mimics APC’s anti-inflammatory activity and endothelial barrier stabilization activity. The objective of this study was to determine whether the G10 peptide mimics APC’s anti-apoptotic activity using cultured murine neurons challenged by N-methyl-d-aspartate that provokes neuronal apoptosis. In these new studies, the G10 peptide mimicked APC’s anti-apoptotic activity. Thus, the PAR-derived 34-residue G10 peptide mimics APC’s three major cytoprotective activities, namely anti-inflammatory and anti-apoptotic activities and endothelial barrier stabilization. Peptides that agonize GPCRs provide promising and currently approved drugs; e.g., semaglutide and tirzepatide that contain 31 and 39 amino acid residues, respectively. Thus, this new study adds to the rationale for pursuing further studies of the G10 peptide for potential therapeutic value for multiple pathologies where APC or signaling-selective APC variants are therapeutic in preclinical animal studies. Full article

This narrative review examines the complex relationship between sleep changes during the menopausal transition and cardiometabolic risks. The most common complaint about sleep is increased awakenings during sleep. Other complaints include having trouble falling asleep, waking up too early, insufficient and non-restorative sleep, and overall poor quality. Sleep determined using objective methods also indicates that greater awakenings after sleep onset are associated with the period of menopausal transition. Polysomnography recordings suggest physiological hyperarousal during sleep. Changes in other sleep metrics, such as sleep latency and sleep duration, are less consistent, and some studies suggest they may not worsen during the menopausal transition. These sleep issues are influenced by multiple factors, such as hormonal fluctuations, vasomotor symptoms, and psychosocial factors, and evidence suggests that hypothalamic kisspeptin/neurokinin B/dynorphin (KNDy) neurons are key underlying mechanisms for these associations. The menopausal transition is also associated with increases in cardiometabolic risk factors, such as body fat, altered lipid profiles, blood pressure, and vascular health. Emerging evidence suggests that poor sleep health during this period is associated with increased cardiometabolic risks and adverse cardiovascular outcomes. Thus, addressing sleep disturbances is crucial for comprehensive healthcare during the menopausal transition to safeguard long-term cardiometabolic health. Future research is needed to investigate interventions that can improve sleep and their impact on cardiometabolic health in this population experiencing increases in cardiometabolic risk. Full article

Oxidative stress and mitochondrial dysfunction are heavily implicated in all forms of Parkinson’s disease; however, antioxidant administration has largely failed in clinical trials. Among the likely causes of failure are brain bioavailability and cellular redox state. We have administered two manganese porphyrin compounds with different bioavailability, MnTE-2-PyP⁵⁺ and MnTnBuOE-2-PyP⁵⁺, to parkin-null Drosophila food and found that the more bioavailable one, with higher brain and mitochondrial availability, MnTnBuOE-2-PyP⁵⁺, improves developmental deficits and motivated behavior in female flies. Using highly sensitive redox reporters, we further found that MnTnBuOE-2-PyP⁵⁺ reduces hydrogen peroxide levels in mitochondria of dopaminergic neurons that are functionally homologous to the mammalian substantia nigra and facilitates motivated behavior in female flies. Interestingly, both compounds reduce an oxidative stress marker at the whole-brain level and extend lifespan in control flies. Neither compound improves lifespan in parkin-null flies. Thus, additional studies, changing the timing and/or dosage of compound administration, are warranted. Full article

Background: Dopamine (DA) is a critical neurotransmitter that regulates many physiological and behavioral processes. The central dopaminergic system plays a pivotal role in modulating general anesthesia (GA). DA release in the brain is mainly concentrated in the nucleus accumbens (NAc), prefrontal cortex, hypothalamus, and dorsal striatum. Several NAc neuron subtypes are essential for modulating states of consciousness during GA. However, whether NAc DA signal dynamics correlate with different states of consciousness under sevoflurane anesthesia remains to be elucidated. In this study, we measured the dynamic fluctuations of NAc DA levels throughout sevoflurane anesthesia to verify its role. Methods: An intensity-based genetically encoded DA indicator, dLight1.1, was employed to track DA release in the NAc. Fiber photometry combined with electroencephalogram/electromyogram recordings was employed to synchronously track NAc DA signal dynamics across different states of consciousness under sevoflurane anesthesia. Results: Under 2.5% sevoflurane exposure, DA release in the NAc significantly increased during the initial 100 s of sevoflurane induction, which was designated as sevo on-1 (mean ± standard error of the mean [SEM]; baseline vs. sevo on-1, p = 0.0261), and continued to decrease in the subsequent anesthesia maintenance phases (sevo on-1 vs. sevo on-4, p = 0.0070). Following the cessation of sevoflurane administration (with intervals denoted as sevooff), NAc DA gradually returned to baseline levels (sevo on-1 vs. sevo off-1, p = 0.0096; sevo on-1 vs. sevo off-3, p = 0.0490; sevo on-1 vs. sevo off-4, p = 0.0059; sevo on-4 vs. sevo off-4, p = 0.0340; sevo off-1 vs. sevo off-4, p = 0.0451). During the induction phase, NAc DA signal dynamics markedly increased during the pre-loss of consciousness (LOC) period (pre-anesthesia baseline vs. pre-LOC, p = 0.0329) and significantly declined after LOC (pre-LOC vs. post-LOC, p = 0.0094). For the emergence period, NAc DA release exhibited a noticeable increase during the initial period after recovery of consciousness (ROC) (anesthesia baseline vs. post-ROC, p = 0.0103; pre-ROC vs. post-ROC, p = 0.0086). Furthermore, the DA signals peaked rapidly upon the initiation of the burst wave and then gradually attenuated, indicating a positive correlation with the burst wave onset during burst suppression events. Conclusions: Our findings revealed that NAc DA neurotransmitter signal dynamics correlate with different states of consciousness throughout sevoflurane anesthesia. Full article