Neurodegenerative disorders involve a strong inflammatory component, yet the underlying inflammatory mechanisms may be heterogeneous across disease stage, cell type, and systemic context. A key unresolved question is how cellular and systemic stress is converted into sustained neuroinflammation. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an innate DNA-sensing hub that translates mislocalized self-DNA - derived from mitochondrial stress and mtDNA leakage, nuclear envelope instability, micronuclei formation, or impaired nucleic-acid disposal - into type I interferon, NF-kB, autophagy-related, and senescence-associated inflammatory programs. Rather than treating cGAS-STING as a universal disease-defining pathway, this review frames it as a context-dependent amplifier that becomes pathogenic when DNA-DAMP burden, defective mitochondrial quality control, neurovascular "leakage", and glial priming converge. We synthesize cell-type-specific evidence in microglia, astrocytes, neurons, and the neurovascular unit; compare mechanistic involvement across Alzheimer's disease, Parkinson's disease dementia and Lewy body disease, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), vascular and acute brain injury, and systemic inflammatory encephalopathies; and organize periphery-to-brain communication axes using an explicit evidence-grading framework. A distinctive contribution of this review is a two-hit model in which systemic inflammatory stressors and barrier dysfunction first lower cognitive resilience, followed by brain-resident mitochondrial/DNA damage programs that lock in complement-linked synaptopathy. We also evaluate pharmacological and lifestyle-based modulation, emphasizing biomarker-enriched trial design, CNS exposure, compartment-specific target engagement, and immune-safety constraints. This framework aims to clarify when, where, and in whom cGAS-STING modulation may preserve synapses and cognition without unacceptable immune trade-offs.

Precise control of membrane protein localization and turnover is essential for synaptic function and circuit stability. Disruption of these processes alters the surface expression of receptors and transporters, ultimately impacting the excitatory/inhibitory (E/I) balance. Leucine-rich repeat kinase 2 (LRRK2) is emerging as a key regulator of these membrane-associated processes, acting at the interface between intracellular trafficking and synaptic signaling. LRRK2 integrates kinase activity with scaffolding functions to coordinate Rab-dependent vesicular trafficking, endosomal recycling, cytoskeletal dynamics, and endolysosomal pathways. Through these mechanisms, it controls the surface expression and distribution of synaptic receptors and neurotransmitter transporters in both neuronal and glial compartments. Pathogenic LRRK2 variants associated with Parkinson's disease (PD), converge on kinase hyperactivation and lead to sustained alterations in trafficking networks, resulting in selective mislocalization of membrane proteins. In this review, we examine how LRRK2-dependent trafficking mechanisms regulate key components of synaptic transmission, including glutamatergic and GABAergic receptors, as well as astrocytic transporters. We highlight how disruption of these processes affects neurotransmitter clearance, receptor activation, and ultimately E/I balance. Notably, accumulating evidence indicates that LRRK2 functions as an upstream coordinator of membrane organization at the crossroads of synaptic signaling and neurotransmitter homeostasis. Understanding how LRRK2 regulates trafficking pathways across cellular compartments provides mechanistic insight into circuit vulnerability in PD and highlights membrane-targeted strategies as potential approaches for restoring synaptic stability.

To explore the effect of esketamine (ES) pretreatment on necroptosis in mice with trigeminal neuralgia accompanied by anxiety-like behavior and its correlation with the RIP1/RIP3/MLKL signaling pathway. Thirty male C57BL/6J mice were randomized into five groups (n=6): Control, Sham, model group (PIONT), PIONT+NS, and PIONT+ES. Trigeminal neuralgia model was established by left infraorbital nerve transection. ES (10 mg/kg, i.p.) was given daily for 5 days preoperatively (preoperative pretreatment) in the PIONT+ES group before molding, and equal-volume saline was administered identically in the PIONT+NS group. Pain thresholds were measured on postoperative days 3, 7, 14 and 21. Behavioral assessments were conducted on day 19, and tissue samples were harvested on day 21. Histopathological staining, immunofluorescence, qPCR, Western blot, ELISA and molecular docking were further performed for subsequent analyses. PIONT group showed reduced pain thresholds, anxiety-like behaviors, neuronal degeneration, decreased dendritic spine density, elevated TNF-α, and upregulated RIP1/RIP3/MLKL (all P<0.05). ES pretreatment prevented the development of these pathological alterations, with improved neuropathology, reduced TNF-α/RIP1/RIP3/MLKL levels, and increased spine density (P<0.05). Molecular docking showed ES binds RIP1/RIP3/MLKL/TNF-α with energies -5.46, -5.10, -5.94, -7.36 kcal/mol. ES pretreatment prevents the development of trigeminal neuralgia and anxiety-like behaviors in mice, which is associated with suppression of necroptosis-related signaling.

This study aimed to investigate whether 5-HT6 receptor (5-HT6R) antagonism could ameliorate epilepsy-associated emotional and behavioral disturbances in rats with temporal lobe epilepsy (TLE) and to explore its potential association with the MEF2C/NF-κB pathway. Thirty rats were randomly divided into normal control (NC) group, Model group and 5-HT6R group. The TLE model was established using lithium chloride-pilocarpine. The rats in 5-HT6R group were treated with 5-HT6R antagonist SB271046. Behavioral tests were conducted to evaluate anxiety- and depression-like behaviors associated with epilepsy. Levels of inflammatory factors, 5-HT and KYN in hippocampal tissues were detected by enzyme-linked immunosorbent assay. Neuronal cell death in brain tissues was assessed by TUNEL staining, and the protein expressions of MEF2C and NF-κB p65 were measured by Western blotting. Molecular docking between SB271046 and MEF2C/NF-κB p65 was performed using AutoDock 4. In addition, JASPAR database was used to analyze the putative binding of CREB1 to MEF2C promoter. Rats in the Model group exhibited significant epilepsy-associated anxiety- and depression-like behaviors, accompanied by aggravated inflammation, decreased MEF2C protein expression and increased NF-κB p65 protein expression. Treatment with SB271046 significantly ameliorated these behavioral abnormalities and inflammatory responses, and was associated with upregulated MEF2C protein expression and downregulated NF-κB p65 protein expression. KEGG enrichment analysis suggested the involvement of NF-κB pathway in TLE. Molecular docking revealed potential interactions between SB271046 and MEF2C/NF-κB p65. 5-HT6R antagonist SB271046 may alleviate epilepsy-associated emotional and cognitive disturbances, potentially through neurostabilizing and anti-inflammatory effects linked to modulation of the MEF2C/NF-κB pathway. These mechanistic associations remain preliminary and warrant further validation using targeted gain- or loss-of-function approaches.

Glutamate (Glu), although the main excitatory neurotransmitter (NT) of the central nervous system (CNS), evidence recognizes its role in influencing immune cell function and activation, including cytokine production, cell proliferation, migration, and survival. Importantly, dysregulation of Glu homeostasis has been implicated in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive cognitive decline, neuronal loss and neuroinflammation. This review synthesizes current evidence on the biochemistry of the glutamatergic synapse, as well as the expression and signaling of Glu receptors (GluRs) in human immune cells. Furthermore, it examines two major hypotheses of AD pathogenesis -the glutamatergic and the neuroimmune hypothesis- and proposes a unified glutamatergic-neuroimmune framework. In this model, disrupted glutamatergic signaling at the neuron-glia-immune interface may represent a central contributor to AD pathology. Understanding the glutamatergic-neuroimmune axis may provide novel insights into therapeutic strategies targeting neuroimmune modulation in AD.

Ketone bodies are a major source of cerebral energy during fasting and the ketogenic diet, but whether they can sustain brain tissue metabolism when glucose is absent remains uncertain. This question is difficult to resolve in vivo because circulating glucose is maintained, even during starvation, through endogenous production. We therefore used an ex vivo brain preparation to examine the metabolic capacity of tissue following incubation with β-hydroxybutyrate (BHB) as the only exogenous fuel, isolating brain tissue from its primary endogenous glucose sources. Mitochondrial respiration was monitored following 4-hour incubation in glucose-free, BHB-rich artificial cerebrospinal fluid, and tissue resilience was tested by inducing spreading depolarization, a severe energetic challenge that requires rapid restoration of ionic and metabolic homeostasis. Following acute reliance on exogenous BHB, in addition to endogenous energy reserves, mitochondrial electron transfer system function persisted, with lower O2 flux than following incubation with exogenous glucose. BHB-supported tissue maintained sufficient energetic capacity to generate and recover from repeated spreading depolarizations. In contrast, tissue relying solely on endogenous energy reserves failed to undergo repeated spreading depolarizations, suggesting that exogenous BHB provided the needed short-term energetic support beyond that available from endogenous substrates in the complete absence of exogenous glucose. The results broaden our understanding of cerebral fuel flexibility and provide evidence that BHB can support highly energetic neural function in the absence of exogenous glucose.

Dementia is clinically and biologically heterogeneous, and genetically supported plasma protein associations across dementia subtypes remain incompletely characterized. We aimed to genetically prioritize plasma proteins associated with overall dementia and major dementia subtypes using proteome-wide Mendelian randomization (MR) and Bayesian colocalization. We used the UK Biobank Pharma Proteomics Project (UKB-PPP) as a harmonized source of cis-protein quantitative trait loci (cis-pQTLs) for 2,941 Olink-measured plasma analytes. The European-ancestry discovery cis-pQTL analysis included up to 34,557 participants, whereas 54,219 participants were profiled in the overall UKB-PPP. Outcomes included FinnGen R10 genome-wide association studies (GWAS) for dementia, Alzheimer's dementia, vascular dementia, frontotemporal dementia, and unspecified dementia, plus a European GWAS for dementia with Lewy bodies. At the nominal threshold of P < 0.05, 134, 132, 102, 78, 101, and 112 exploratory protein-outcome signals were observed for dementia, Alzheimer's dementia, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, and unspecified dementia, respectively; 23 associations remained significant after outcome-specific Benjamini-Hochberg false discovery rate (FDR) correction. Key FDR-significant proteins included APOE, NECTIN2, PVR, SERPINF2, GRN, TREM2, and ATXN2L. The strongest risk and protective associations were NECTIN2 with Alzheimer's dementia (odds ratio [OR] = 2.650, 95% confidence interval [CI]: 1.875-3.744, FDR-adjusted P = 1.58 × 10[- 5]) and ATXN2L with dementia (OR = 0.408, 95% CI: 0.255-0.654, FDR-adjusted P = 0.0370), respectively. Strong colocalization support was observed for selected SERPINF2 and TREM2 associations. These findings genetically prioritize several plasma proteins as candidate biomarkers and potential therapeutic targets across dementia subtypes, but do not establish that circulating protein abundance directly mediates dementia risk.

One of the major challenges in neuroscience is understanding how the human brain develops into a highly organized and functionally integrated organ, because many developmental processes cannot be investigated directly in humans and are not fully recapitulated in animal models. Brain organoids derived from human pluripotent stem cells have emerged as powerful three-dimensional (3D) experimental models that recapitulate key features of human neurodevelopment, including regional patterning, cellular diversification, and neural circuit assembly. Recent advances in long-term organoid culture, organoid bioengineering, vascularization, assembloid technology, transplantation, multi-omics, and artificial intelligence have substantially expanded the applications of brain organoids to investigate human neurodevelopment, model neurological disorders, support drug discovery, and advance therapeutic development. Integration of single-cell and spatial multi-omics with computational approaches has enabled robust molecular benchmarking, assessment of developmental fidelity, and evaluation of organoid reproducibility, facilitating direct comparison with primary human fetal brain tissue. However, current organoid systems remain limited owing to incomplete cellular and tissue complexity, inter-organoid variability, limited vascularization, limited functional maturation, and incomplete physiological integration. Continued advances in tissue engineering, computational biology, and standardized differentiation protocols are expected to enhance the biological fidelity and translational utility of brain organoids for basic and translational neuroscience, as well as mechanistic and translational research.

Mitochondria integrate metabolic, signalling, and quality-control pathways that are critical for neuronal and glial homeostasis. Beyond ATP production, they regulate redox balance, calcium dynamics, proteostasis, innate immune signalling, and the molecular pathways governing cell survival and death. This Closing Editorial synthesizes the main advances reported in this Collection across neurodegeneration, neurodevelopmental vulnerability, inherited mitochondrial disorders, neurotrauma, drug-induced neurotoxicity, and neuroimmune regulation. Collectively, these studies establish mitochondrial dysfunction as a heterogeneous and context-dependent process rather than a uniform or secondary consequence of neurological disease. Mitochondrial alterations are dynamically regulated across cell types, subcellular compartments, and disease stages, and are tightly coupled to inter-organelle communication and cellular stress-response pathways. The contributions highlight convergent mechanisms linking astrocytic mitochondrial DNA damage, dysregulated RNA-binding proteins, altered mitochondria-endoplasmic reticulum contacts, disrupted iron and redox homeostasis, and mitochondrial-inflammatory signalling to neuronal vulnerability and impaired circuit integrity. They also identify potential therapeutic targets while defining key unresolved questions, particularly the need to establish mechanistic causality, delineate cell- and compartment-specific mitochondrial responses, and validate findings using clinically relevant models and outcome measures. Overall, this Collection positions mitochondrial biology as a mechanistic framework connecting metabolic dysfunction, cellular stress, neuroinflammation, and neuronal degeneration, and supports its development as a therapeutic target for disease-modifying interventions in neurological disorders.

The targeted differentiation of stem cell-like cells into functional neurons is a central goal in developmental biology and comparative neurobiology. In this study, we report for the first time on the successful neuronal remodeling of cell line derived from the Atlantic sturgeon larvae (Acipenser oxyrinchus; AOXlar7y) under defined in vitro conditions. The cells were cultured on poly-D-lysine-coated surfaces and exposed to a reduced-serum medium supplemented with nerve growth factor-β to induce neuronal differentiation. Morphologically, time-dependent formation of neurite-like processes and network structures was observed over a period of 14 days. The neuronal identity of the differentiated cells was confirmed by immunocytochemistry with the neuronal marker NeuN. Functional maturation was examined by measurement of cytoplasmatic calcium activity. After stimulation with 200 µM ATP, cells with neuronal morphology showed distinct intracellular calcium transients, indicating functional purinergic signaling pathways. AOXlar7y thus represents a novel in vitro model for studying neurogenesis and neuronal function in a cellular model of ancient fish species and provides a valuable basis for future studies in comparative neurobiology, neurotoxicology, and evolutionary developmental biology.

Peripheral nerve injury (PNI) disrupts nerve function, there has been increasing focus on the role of macrophages in PNI. This study provides a comprehensive analysis of research trends and key topics related to macrophages in the field of PNI. We conducted a search in the Web of Science Core Collection database for studies published between 2000 and 2023 using "macrophages" and "PNI" as keywords. Bibliometric analysis was performed using visualization tools, including VOSviewer, CiteSpace, and GraphPad Prism 8, and others. As of December 31, 2023, a total of 905 relevant publications were identified. In terms of author contributions, Japanese researchers Kiguchi Norikazu and Kishioka Shiroh shared the highest number of publications, each with 15 articles. In terms of journals, Experimental Neurology published the most articles, while the University of Würzburg in Germany emerged as the leading institution in this field, with the highest publication output. Among the 51 countries involved in this research, the United States ranked first, followed by China. The keyword 'exosomes' first appeared in 2021, making it the most recent keyword. Cluster analysis categorized the keywords into four main groups: the role of macrophages in Wallerian degeneration, the role of macrophages in pathological peripheral neuropathic pain, macrophage-derived products after PNI, and role of macrophages in PNI repair and strategies for modulating their function using biomaterials. Macrophages are increasingly crucial in PNI research, and future studies integrating novel approaches may yield innovative therapies for nerve repair.

Alzheimer's disease (AD) is a neurodegenerative disorder characterised by progressive dementia, brain atrophy, and ultimately death. Using cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) carrying the familial PSEN1 A246E variant, we investigated the temporal relationship between amyloid-β (Aβ) dysregulation and spontaneous neuronal activity. Multielectrode array recordings from the differentiation day 60 (DD60) to at least DD130 revealed that AD organoids exhibited transient hyperexcitability and hypersynchrony compared with wild-type (WT) controls, followed by a gradual decline in activity. During the enhanced excitability stage, both elevated Aβ42/40 and Aβ aggregate size showed positive correlations with the percentage of active electrodes and the global synchrony index (GSI) in AD organoids. These findings indicate that Aβ dysregulation might contribute to transient network hyperexcitability in early AD. The results also suggest that patient-derived cerebral organoids may serve as a translational model to examine early network dysfunction and inform future investigations of potential Aβ-induced changes in excitability during the preclinical stages of AD.

Fumaric acid esters have proven to be effective medications in relapsing-remitting multiple sclerosis with neuroprotective effects. In this study, we investigated the impact of fumaric acid esters on primary murine microglia in vitro compared to DMSO vehicle control. Monomethyl fumarate (MMF) increased MTT reduction in a dose-dependent manner, whereas dimethyl fumarate (DMF) exhibited a biphasic response with low concentrations enhancing MTT reduction and higher concentrations inducing toxicity. Notably, complementary analyses of cell number and cell death did not reveal differences between MMF-treated and control conditions, indicating that the increased MTT reduction reflects enhanced cellular metabolic activity rather than increased viability. Consistent with this interpretation, MMF-treated cells exhibited higher basal and maximal oxygen consumption, spare respiratory capacity, and ATP production in the Seahorse XF Cell Mito Stress Test. Proteomic analysis did not indicate an upregulation of mitochondrial respiratory chain proteins, but instead suggested a qualitative shift in mitochondrial homeostasis, including increased expression of mitophagy-associated proteins. MMF-treated Nrf2-deficient microglia showed a blunted increase in MTT reduction, suggesting an involvement of Nrf2 in mediating MMF-induced metabolic effects. Additionally, MMF modulated the microglial iron metabolism and reduced the uptake of non-transferrin-bound iron and altered the gene expression of iron transport proteins, promoting a shift toward the uptake of less toxic, transferrin-bound iron. MMF mitigated iron-induced toxicity and was associated with upregulation of the ferroptosis suppressor protein, indicating a protective response to iron overload. Together, these findings suggest that MMF enhances microglial metabolic activity and mitochondrial function while reducing iron-mediated toxicity, thereby contributing to its neuroprotective effects.

Mitochondrial dysfunction has been recognized as one of the three hallmark biological features of autism spectrum disorder. This study is intended to investigate the molecular mechanisms underlying prenatal psychological fear stress‑induced hippocampal mitochondrial damage in offspring. Bioinformatics analysis revealed that the calcium signaling pathway, particularly the phospholipase C beta 1(PLCβ1)- inositol 1,4,5‑trisphosphate receptor (IP3R)- voltage‑dependent anion channel 1(VDAC1) pathway, may play a key role in prenatal stress‑induced hippocampal mitochondrial damage in offspring. To validate this, we examined pathway activation in the offspring hippocampus of prenatal fear stressed rats and in corticotropin-releasing hormone (CRH; also known as CRF in rodents) overexposed SH‑SY5Y cells, along with mitochondrial calcium levels in the cells. Prenatal fear stress induced depressive-like behavior and HPA axis activation in pregnant dams, and reduced survival and growth in offspring. Placental and neonatal brain CRF levels were elevated. At the early socialization stage (Postnatal day 21-30), model offspring showed normal basal but exaggerated stress-induced HPA responses. Their hippocampus exhibited expanded MAM coverage, reduced ER-mitochondria distance, and upregulated PLCβ1, IP3R1, VDAC1 expression, along with increased GRP75‑VDAC1 co‑localization, confirming MAM remodeling at the molecular level. In vitro, CRH (20 µM for 48 h or 5-20 µM for 96 h) inhibited SH-SY5Y cell proliferation, upregulated CRH receptor 1(CRHR1), PLCβ1, VDAC1, and increased mitochondrial calcium; these effects were reversed by the CRHR1 antagonist CP376395 or PLCβ1 knockdown. Furthermore, the MCU inhibitor DS16570511 partially reversed CRH‑induced mitochondrial calcium elevation and proliferation inhibition, suggesting that mitochondrial calcium overload contributes to the proliferation inhibition. Collectively, these results suggest that prenatal fear stress may, via the CRF-CRFR1 axis, influence the PLCβ1-IP3R-VDAC1 pathway, inducing MAM remodeling and mitochondrial calcium overload, thereby contributing to offspring hippocampal neuronal damage.

Early-life nutrition is increasingly recognized as a key determinant of brain developmental trajectories. Because the dorsal (dHIP) and ventral (vHIP) hippocampus regulate distinct cognitive and emotional functions, understanding how maternal diet shapes maturation along this axis may provide insight into later behavioral vulnerability. However, the impact of maternal diet on the spatial organization of hippocampal maturation along the dorsal-ventral axis remains unclear. Here, we tested whether maternal isocaloric monosaccharide diets containing glucose (GLU) or fructose (FRU) are associated with age-, sex-, and region-dependent molecular remodeling along the dorsal-ventral axis of the hippocampus. In an established Wistar rat cohort, we quantified mRNA expression of genes associated with neuronal maturation and plasticity (Bdnf, Dcx, Gfap, Nes, Rbfox3) and protein levels of DCX, GFAP, and NeuN in the dHIP and vHIP of dams and male and female offspring during adolescence (PND28) and young adulthood (PND63). In dams, FRU exposure was associated with modestly increased Bdnf expression, and both GLU and FRU diets were associated with region-dependent differences in DCX, GFAP, and NeuN protein levels. In offspring, perinatal exposure to GLU or FRU diets induced sex-dependent patterns of hippocampal gene expression. Diet-related molecular differences were more prominent in the dHIP during adolescence, whereas additional vHIP-associated alterations emerged in young adulthood. Several proteins exhibited region-dependent differences, with the vHIP generally displaying higher protein abundance, although diet-induced alterations differed between hippocampal subregions. Guided by PCA and a composite RNA-protein molecular index highlighting persistent molecular remodeling within the vHIP, subsequent analyses focused on the vHIP in male offspring. Targeted analysis of the male vHIP at PND63 revealed that maternal FRU exposure was associated with increased Mc4r expression and elevated MC4R protein levels, whereas both maternal GLU and FRU exposure were associated with increased ARC protein levels. In contrast, maternal monosaccharide exposure was associated with reduced Npas4 expression, and maternal FRU exposure was additionally associated with reduced NPAS4 protein levels. Collectively, maternal monosaccharide diets were associated with age-, sex-, and region-dependent remodeling of hippocampal maturation- and plasticity-related molecular profiles. Subsequent analyses identified persistent alterations in MC4R-, ARC-, and NPAS4-related molecular profiles in the young adult male vHIP.