Alzheimer's disease is a complex neurodegenerative disorder characterized pathologically by amyloid-β deposition and pathological tau aggregation. Amyloid-β deposition typically occurs during the preclinical stage; however, amyloid burden does not exhibit a simple linear relationship with neurodegeneration or cognitive decline. In contrast, the spatial distribution of tau pathology is more closely associated with clinical progression. As the resident innate immune cells of the central nervous system, microglia participate in the recognition, uptake, and containment of amyloid-β and tau. Nevertheless, persistent exposure to damage-associated signals can lead to lysosomal dysfunction, dysregulated lipid metabolism, and mitochondrial impairment in microglia, thereby amplifying neuroinflammation, aberrant synaptic elimination, and neuronal injury. The traditional binary M1/M2 classification is inadequate to capture the continuous, overlapping, and context-dependent functional states of microglia, which vary across brain regions, genetic backgrounds, and disease stages. This review integrates recent evidence from genetic, single-cell/single-nucleus, and spatial transcriptomic studies and proposes a "cellular state-pathological network-therapeutic window" framework. We systematically discuss the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA-cGAS-STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia-tau feedback. On this basis, we critically evaluate the mechanistic rationale, stage dependence, and translational limitations of therapeutic axes involving TREM2/CD33, P2X7-NLRP3 and cGAS-STING, CSF1R/complement, and TNF-TNFR1-RIPK1. Current evidence suggests that the key to microglia-targeted therapy is not the broad activation or suppression of immune responses, but rather the biomarker-guided and disease-stage-specific modulation of pathogenic signaling while preserving homeostatic functions such as plaque containment, debris clearance, synaptic maintenance, and tissue repair.
BackgroundBFP, bifacial weakness with paresthesias is a rare variant of Guillain-Barré syndrome (GBS). Here, we detail the diagnosis and treatment process of a patient with BFP secondary to head trauma to highlight its importance.CaseA 47-year-old man presented with bilateral peripheral facial paralysis, hearing loss, and sensory impairment in both lower limbs following a car accident. Temporal bone fracture was first considered as the cause of facial palsy. We gave glucocorticoid therapy to the patient, but it was ineffective, facial nerve decompression surgery was planned as a consideration. However, diminished tendon reflexes was noted on the 12th day post-trauma, then cerebrospinal fluid (CSF) testing and anti-ganglioside antibodies were performed. Based on the medical history and Laboratory testing, the patient was diagnosed with BFP, a rare variant of GBS. Plasma exchange therapy was performed on the patient. At six-month follow-up, except for hearing loss, the other symptoms had almost returned to normal.ConclusionIn this article, we report a case of BFP secondary to head trauma. We emphasize that in patients with post-traumatic bilateral facial nerve paralysis, a comprehensive neurological examination is essential for accurate diagnosis and to avoid unnecessary medications or surgery.
Substance use disorders (SUDs) remain major public health concerns worldwide, particularly in developed countries. SUDs are characterized by persistent neuroinflammation and synaptic dysfunction in the brain. Despite decades of extensive investigation, the detailed mechanisms underlying SUDs remain elusive. Ferroptosis is a highly regulated cell death process deeply affected by iron metabolism, lipid peroxidation, reactive oxygen species (ROS) production, and antioxidant systems. It has been implicated in multiple neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemic stroke. Recently, emerging evidence has highlighted the role of ferroptosis in drug-induced pathological changes. Various types of abused substances including alcohol, cocaine, methamphetamine (METH) nicotine, cannabis, and opioids have been shown to disrupt ferroptosis-relevant pathways, leading to microglial activation and neuronal injury. Inhibition of ferroptosis could mitigate these pathological changes in preclinical models. Here, we summarize current evidence demonstrating the effects of abused drugs on ferroptosis pathways. Collectively, these findings underscore the potential role of ferroptosis in the pathophysiology of SUDs. Targeting ferroptosis may represent a promising therapeutic strategy for alleviating drug-induced neurological damage and improving recovery outcomes such as cognitive and memory deficiency in individuals with addiction.
Despite long-standing investigations into the neural and molecular correlates of memory, there persists a lack of comprehensive understanding of the cellular and subcellular processes that go awry in cases of neurodivergent and neuropathological phenotypes. While the mechanisms of memory encoding, consolidation, and retrieval are well-characterized in neurotypical models, disruptions in these processes often manifest as cognitive dysfunctions in the contexts of neurodevelopment and neurodegeneration. In this review, we specifically examine the molecular frameworks of memory processing arising from neurodevelopmental disorders. Given that developmental disorders affecting early stages of neural circuitry formation are manifested much later, in the adolescent or adult stages of life, it is important to delineate exactly how the molecular underpinnings of memory formation lead to atypical behavioral phenotypes manifested in different neurodevelopmental conditions. By integrating behavioral phenotypes with underlying circuit and molecular pathologies, this paper argues for a multiscale perspective to understand and address the divergence between neurotypical and neurodivergent memory function.
Choroid plexus epithelial cells (CPEC) are implicated in cerebrospinal fluid (CSF) production and the site of the inner blood-cerebrospinal fluid barrier. CPEC are specialized ependymal cells with characteristic cell junctions, intermediate filaments, and transport protein expression, including aquaporins. We have recently found that, in addition to aquaporin-1, a subset of CPEC in the human brain express aquaporin-4 (AQP4), the main water channel in the brain that has been implicated in water homeostasis and glymphatic system function. We therefore aimed to establish primary cultures from human CP to study AQP4 expression. We collected CP tissue from human body donors post mortem to grow CPEC in vitro. We successfully established two primary culture models for human CP tissue. In an organ culture model, small pieces of CP tissue were explanted on PTFE membranes. In a second model, cells from CP were dissociated and seeded on either laminin or collagen substrate. We monitored cell and tissue growth and investigated protein expression by immunofluorescence. Tissue integrity of explant cultures was maintained throughout the cultivation period of several weeks. Immunofluorescence signals for zonula occludens protein-1 (ZO1), AQP1, and Na/K-ATPase were present although the expression patterns became increasingly irregular and non-polar over time. In dissociation cultures, cells attached and grew very slowly initially but reached confluency after several weeks. Cultures were passaged up to 6 times and could be cryopreserved. Application of cytosine arabinoside suppressed the growth of macrophages and most likely fibroblasts. These primary dissociation cultures were identified as epithelial by their morphology and positive immunofluorescence for transthyretin, vimentin. Na/K-ATPase, ZO-1, cytokeratin, and AQP1. In both culture models, cells expressed AQP4. In dissociation cultures, AQP4 appeared to colocalize with ZO-1 at cell–cell contact sites in many CPEC but showed separate localizations at high resolution. These studies show that primary organ and cell cultures can be generated from human post mortem CP tissue suitable to investigate regulation and localization of AQP4. Together, these culture models provide valuable tools to investigate the proteins involved in CSF production and glymphatic clearance, relevant for the pathogenesis of neurodegenerative diseases.
IntroductionPeroxisomes are highly dynamic organelles that contribute to cellular homeostasis by coordinating lipid metabolism, reactive oxygen species handling, and adaptive responses to metabolic stress. Their plasticity is particularly relevant in the nervous system, where peroxisomes cooperate with mitochondria to maintain redox and metabolic balance in neuronal and glial cells. Peroxisome proliferator-activated receptor alpha (PPARα), together with its coactivator PGC-1α, represents a major transcriptional regulator of peroxisomal and mitochondrial metabolic programs.MethodsBV2 microglial cells were exposed to rotenone to investigate how mitochondrial oxidative stress influences the peroxisomal compartment. Mitochondrial and peroxisomal morphology, intracellular distribution, oxidative damage, and the expression of proteins involved in peroxisomal metabolism and PPARα signaling were evaluated.ResultsRotenone induced a stress-associated microglial phenotype characterized by cytoskeletal remodeling, mitochondrial network disruption, and oxidative damage. These alterations were accompanied by a coordinated reorganization of the peroxisomal compartment, including increased abundance of peroxisomal membrane markers, redistribution of peroxisomes toward the perinuclear region, and enhanced expression of enzymes associated with peroxisomal fatty acid oxidation. An increased spatial association between peroxisomes and mitochondria was also observed, suggesting that peroxisomal remodeling forms part of a broader inter-organelle adaptation to mitochondrial dysfunction. These changes occurred together with increased nuclear phosphorylated PPARα and enhanced PGC-1α immunoreactivity, supporting the engagement of a PPARα–PGC-1α-related transcriptional response.DiscussionOverall, our findings suggest that mitochondrial dysfunction in microglial cells activates a PPARα-associated adaptive program that promotes peroxisomal remodeling and strengthens mitochondria–peroxisome coordination. This response may represent an attempt to preserve lipid and redox homeostasis during cellular stress and identifies PPARα-regulated peroxisomal pathways as potentially relevant components of microglial metabolic adaptation in neurodegenerative conditions.
BackgroundAnimals must learn not only which cues predict reward, but also when to act to obtain it. Although the orbitofrontal cortex (OFC) encodes reward-related information, whether reward contingency is sufficient to reorganize the temporal alignment of OFC activity remains unclear.MethodsWe recorded calcium signals from lateral OFC pyramidal neurons (lOFC-PNs) in wild-type (WT) and Sapap3 knockout (KO) mice using fiber photometry, during sequential learning of Pavlovian and instrumental contingencies in a single-odor reward association task. We further used a cue-free lick test and linear mixed-effects modeling to dissociate the contribution of reward contingency from that of licking behavior.ResultsLicking behavior and lOFC-PN activity were comparable between WT and KO mice, supporting pooled analysis. Under Pavlovian contingencies, licking and lOFC-PN activity were concentrated around reward delivery. Under instrumental contingencies, both shifted to the pre-reward delay period, and the timing of lOFC-PN activity became progressively coupled to anticipatory licking as learning advanced. A cue-free lick test and linear mixed-effects modeling confirmed that these contingency-related differences reflected reward contingency rather than licking per se.ConclusionThese findings indicate that reward contingency dynamically reorganizes the temporal alignment of lOFC-PN activity and its coupling with behavior, shifting from reward-aligned under Pavlovian learning to action-aligned under instrumental learning. This contingency-dependent temporal reorganization may support flexible adaptation of neural processing to changing reward contingencies during associative learning.
The capacity of the olfactory epithelium (OE) to sustain adult neurogenesis offers an unprecedented opportunity to investigate the mechanisms of neural lineage specification, cellular turnover, and tissue regeneration in a human context. Unlike conventional brain organoids, which predominantly model embryonic or fetal neurodevelopment, olfactory organoid systems uniquely provide experimental access to active adult human neurogenic and regenerative dynamics. As the only accessible adult neural stem cell niche that can be repeatedly sampled from living patients, this neuroepithelium opens new paths for generating patient-specific, non-reprogrammed neural models. This review provides an overview of OE-derived in vitro systems, detailing their evolution from early neurospheres to advanced three-dimensional (3D) organoids, highlighting their capacity to preserve donor genetic, epigenetic, transcriptomic and proteomic signatures, establishing them as a powerful platform for personalized medicine, disease modeling, and “nose-to-brain” therapeutic discovery.
Alzheimer’s disease is a complex neurodegenerative disorder characterized pathologically by amyloid-β deposition and pathological tau aggregation. Amyloid-β deposition typically occurs during the preclinical stage; however, amyloid burden does not exhibit a simple linear relationship with neurodegeneration or cognitive decline. In contrast, the spatial distribution of tau pathology is more closely associated with clinical progression. As the resident innate immune cells of the central nervous system, microglia participate in the recognition, uptake, and containment of amyloid-β and tau. Nevertheless, persistent exposure to damage-associated signals can lead to lysosomal dysfunction, dysregulated lipid metabolism, and mitochondrial impairment in microglia, thereby amplifying neuroinflammation, aberrant synaptic elimination, and neuronal injury. The traditional binary M1/M2 classification is inadequate to capture the continuous, overlapping, and context-dependent functional states of microglia, which vary across brain regions, genetic backgrounds, and disease stages. This review integrates recent evidence from genetic, single-cell/single-nucleus, and spatial transcriptomic studies and proposes a “cellular state–pathological network–therapeutic window” framework. We systematically discuss the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA–cGAS–STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia–tau feedback. On this basis, we critically evaluate the mechanistic rationale, stage dependence, and translational limitations of therapeutic axes involving TREM2/CD33, P2X7–NLRP3 and cGAS–STING, CSF1R/complement, and TNF–TNFR1–RIPK1. Current evidence suggests that the key to microglia-targeted therapy is not the broad activation or suppression of immune responses, but rather the biomarker-guided and disease-stage-specific modulation of pathogenic signaling while preserving homeostatic functions such as plaque containment, debris clearance, synaptic maintenance, and tissue repair.
Many Veterans who experienced blast-related traumatic brain injuries (TBI) during their military service suffer from chronic cognitive and mental health problems including post-traumatic stress disorder (PTSD). Male rats exposed to repetitive low-level blast injuries designed to mimic the type of blast-related mild TBI that was so common in the conflicts in Iraq and Afghanistan develop delayed and persistent cognitive and PTSD-related traits that remain present for over 1 year after exposure. Boldine, an alkaloid derived from the Chilean Boldo tree (Peumus boldus), is a widely used herbal remedy with anti-oxidant, anti-inflammatory, hepatoprotective, and connexin hemichannel-blocking properties. We studied whether oral administration of boldine prevented development of PTSD-related behavioral traits in rats exposed to repetitive low-level blast. Treatment with boldine prevented appearance of the blast-induced PTSD-like phenotype including object recognition deficits and exaggerated cued fear learning. Boldine also prevented blast-induced elevation of the metabotropic glutamate receptor 2 (mGluR2) and the N-methyl-D-aspartate receptor 2b (NMDAR2b), but did not reverse decreases in the serotonin 5-HT2A receptor. Iba1 immunofluorescence staining suggested that boldine reduced blast-associated microglial process retraction (indicative of activation) in the somatosensory cortex. Transcriptomics analysis of hippocampus mRNA did not identify individual genes that remained significant after FDR correction. Exploratory analysis of 85 nominally significant candidates suggested that boldine induced coordinated transcriptional changes related to GO terms “Cognition” and “Neurotransmitter Transport,” consistent with modulation of activity-regulated transcription factors and neuroimmune signaling. These studies suggest that boldine may be beneficial for the neurobehavioral syndromes that follow blast exposure in military Veterans.
Accumulation of amyloid-beta (Aβ) deposits is one of the neuropathological hallmarks of Alzheimer’s disease (AD), the most frequent neurodegenerative disease in all age groups. While decades of research have focused on the production and aggregation of Aβ peptides, mounting evidence implicate impaired brain fluid dynamics and protein waste clearance as critical contributors to AD pathogenesis. The aquaporin family of water channels, particularly aquaporin-4 (AQP4) and AQP1, has emerged as central regulators of brain interstitial fluid (ISF) homeostasis and Aβ clearance. AQP4, expressed at the perivascular endfeet of astrocytes, is the principal water channel driving fluid convection exchange, acting as a brain-wide network in which ISF and solutes are cleared via venous, paravenous and periarterial routes, as well as through dural lymphatic vessels and along perineural spaces. AQP1, expressed predominantly in the choroid plexus epithelium, governs cerebrospinal fluid (CSF) secretion and thereby modulates the pressure gradients that sustain this convective flow. This review provides an integrated overview of the molecular pathology of AD, the physiological roles of AQP4 and AQP1, together with the major anatomical pathways of ISF and CSF drainage from the brain. We next address to the genetic and pharmacological modulation of AQP4 and AQP1 in transgenic AD mouse models and describe the resulting pathological changes. AQP4 knockout consistently exacerbates Aβ pathology and cognitive deficits, with the abnormal distribution of AQP4 within the astrocyte being sufficient to impair clearance, and these data highlight the critical importance of polarized expression versus bulk expression levels. AQP1 modulation, though less studied, alters CSF dynamics and may influence Aβ clearance indirectly through changes in CSF turnover. Pharmacological agents targeting AQP4 and AQP1 offer promising avenues for therapeutic intervention. Understanding the distinct and intersecting roles of aquaporins in brain fluid homeostasis may yield novel strategies for restoring protein clearance in AD.
Despite the success of combined antiretroviral therapy (cART) in achieving peripheral viral suppression, HIV-associated neurocognitive disorder (HAND) remains a persistent challenge, affecting approximately 50% of people living with HIV. This review identifies the prefrontal cortex (PFC) as a primary target of HIV-1 neurotoxicity, as HIV-1 can directly infect the brain, and cART fails to eliminate the production of viral proteins from latent HIV-microglial reservoirs. The blood–brain barrier receives several hits from HIV-1 proteins, leading to a leaky and highly permeable barrier. Several proteins drive chronic neuroinflammation through inflammasome activation and pyroptosis, and ferroptosis in microglia. Glutamatergic dysregulation in the CNS results in increased neuron excitability and neurotoxicity. Also, overactive complement-mediated synaptic pruning and microglial senescence disrupt the intricate neural networks required for higher-order signaling. Neuroimaging and PFC dysfunction can be linked to specific HIV-1 proteins and their effects on the brain. Clinical symptoms of HAND directly reflect specialized PFC dysfunction. Deficits include impaired executive processes, which can present as lacking foresight for goal-directed actions, poor planning, and difficulty switching between tasks. Significant behavioral changes, including disinhibition, impaired moral reasoning, and increased risk-taking, can also be seen. Patients experience apathy, emotional blunting, and rapid mood shifts. Cognitive impairments include working memory loss, distractibility, and inappropriate memory linking. PFC disruptions can escalate into neuropsychiatric sequelae, driven by damaged dopamine and serotonin pathways. Defining these viral-mediated mechanisms will facilitate the development of pharmacological strategies that target several HIV-mediated neurotoxic pathways to prevent the debilitating characteristics of HAND.
The subgranular zone (SGZ) of the hippocampus represents a principal site of adult neurogenesis and exhibits distinct structural and organizational features. Increasing evidence indicates that neural stem cell (NSC) behavior in the SGZ is not solely determined by intrinsic cellular properties, but is critically shaped by its surrounding neurogenic niche. However, current studies largely describe niche-derived regulatory factors in isolation, and a systematic framework integrating these diverse signals remains lacking. In this review, we propose a structured perspective that links the unique anatomical and organizational characteristics of the SGZ to its regulatory mechanisms. We conceptualize SGZ niche regulation as a multi-dimensional and non-hierarchical system, in which multiple interacting components—including spatial organization, metabolic–vascular support, neural circuit activity, immune modulation, and extracellular matrix–mediated signaling—collectively govern NSC state transitions. Within this framework, neurogenesis is understood as an emergent outcome of coordinated changes across these regulatory dimensions rather than the result of single-factor control. We further discuss how shifts in the neurogenic niche under pathological conditions—such as aging, Alzheimer’s disease, and chronic cerebral hypoperfusion (CCH) —reshape NSC behavior, driving maladaptive responses that may ultimately lead to dysregulated neurogenesis. By providing a modular and system-level perspective, this review offers a conceptual basis for understanding SGZ regulation and may help identify potential targets for restoring neurogenic capacity.
BackgroundBlood–brain barrier (BBB) disruption is a hallmark of acute traumatic brain injury (TBI), yet the immune–vascular mechanisms underlying endothelial dysfunction remain incompletely understood. Perivascular macrophages (PVMs) are strategically positioned to modulate cerebrovascular homeostasis, but their role in acute post-traumatic endothelial activation has not been systematically characterized.MethodsWe re-analyzed a publicly available mouse single-cell RNA sequencing (scRNA-seq) dataset (GSE290150, 24 h post-TBI) to characterize the landscape of immune and vascular cell populations and to infer intercellular communication. Bone marrow–derived macrophages (BMDMs) served as a PVM surrogate model, and bEnd.3 cerebral endothelial cells were used for in vitro validation of key signaling pathways.ResultsSingle-cell analysis revealed concurrent expansion of PVM-like cells and activated endothelial cells (Activated ECs) in the TBI brain, with CellChat-predicted enhancement of MIF–ACKR3 signaling from PVM-like cells toward Activated ECs. Inflammatory stimulation of BMDMs significantly increased MIF expression and secretion in a STAT3-dependent manner. Macrophage-conditioned medium induced endothelial activation–associated molecular changes, including upregulation of Angpt2 and Adm and downregulation of tight junction genes Claudin5 and Tjp1; these effects were attenuated by MIF inhibitor ISO-1 or ACKR3 antagonist CCX771. Recombinant MIF dose-dependently reproduced these changes, which were substantially abrogated by ACKR3 pharmacological blockade or siRNA knockdown. STAT3 inhibition further suppressed rMIF-induced endothelial transcriptional responses.ConclusionThese findings provide transcriptomic and in vitro evidence supporting a PVM-derived MIF–ACKR3–STAT3 signaling axis associated with endothelial activation–related molecular changes in acute TBI. Direct functional effects on BBB integrity and in vivo relevance require further validation. This candidate axis highlights perivascular immune–vascular crosstalk as a potential avenue for therapeutic investigation.
Sensorineural hearing loss, affecting over 1.5 billion people worldwide, results largely from irreversible damage to inner ear hair cells—specialized mechanosensory receptor cells that mammals cannot spontaneously regenerate. While recent advances in gene therapy and stem cell biology have raised hopes for biological repair, the rapid expansion of research has made it difficult to identify overarching trends, knowledge gaps, and translational bottlenecks. This study provides the first bibliometric analysis focusing on inner ear hair cell regeneration, covering 1,035 publications identified from the Web of Science Core Collection after systematic screening. To ensure the robustness of the findings and assess the sensitivity of the findings to database choice, we performed cross-database validation using Scopus and PubMed, which revealed high overlap rates (82.65% for PubMed and 75.76% for Scopus) and consistent patterns in the non-overlapping subset, suggesting that the primary WoSCC-based findings are not qualitatively altered by the inclusion of literature from other major databases. Using VOSviewer and CiteSpace, we analyzed publication trajectories, country/institution contributions, collaboration networks, and keyword dynamics. The results reveal a sustained increase in annual output, with the United States and China emerging as the two most productive and collaboratively central countries in the global research network. Keyword burst analysis shows a temporal shift from structural characterization (early 2010s) to signaling pathways (mid-late 2010s), and more recently to pathological mechanisms and protective strategies (late 2010s-present), including synaptopathy, transplantation, protection, ototoxicity, replacement, autophagy, and disease. VOSviewer co-occurrence analysis further reveals thematic clusters centered on hair cell regeneration and signaling, ototoxic injury and protection, and gene therapy and delivery, suggesting a field expanding from basic mechanisms toward translational research. These findings demonstrate that the field has diversified from a predominant emphasis on cellular regeneration toward broader attention to functional reconstruction of the hair cell–spiral ganglion neuron synapse. This transition underscores a growing emphasis on multi-target synaptic integration and highlights an unmet need for immune-compatible, subtype-specific gene delivery systems. Overall, this analysis, supplemented by cross-database consistency checks, provides a quantitative roadmap.
The survival motor neuron (SMN) protein is an essential and highly versatile assembly factor that coordinates RNA metabolism and ribonucleoprotein (RNP) complex formation across multiple cellular compartments. Although SMN is required for the survival of virtually all cell types, its deficiency disproportionately affects α-motor neurons, causing their selective degeneration and giving rise to spinal muscular atrophy (SMA). Once viewed primarily as a motor neuron disease, SMA is now understood to be a multi-systemic disorder in which cell-intrinsic dysfunction extends to skeletal muscle, inflammatory glial cells, and metabolic organs. This review examines the regulatory mechanisms that control SMN protein stability, collectively termed proteostasis, with a focus on how post-translational modifications coordinate with the ubiquitin-proteasome system and the autophagy-lysosomal pathway to govern protein turnover and clearance. We also address the emerging concept of gene dosage sensitivity, including the underappreciated paradox that therapeutic SMN overexpression can be as harmful as deficiency, producing distinct toxicities in both neuromuscular and peripheral tissues. Finally, we highlight the need for next-generation combination therapies that integrate genetic modifiers, targeted degradation strategies, and post-translational regulators to maintain SMN levels within the narrow physiological range required for safety and efficacy.
