Molecular Neurobiology最新文献

{"title":"Mast Cells in Neuroimmune Interactions: Mechanisms, Pathophysiological Roles, and Therapeutic Implications.","authors":"Ahmed Hasan, Abd Al Rahman Asfour, Hafsah Qaba, Amal A Al-Sharabi, Adel Asfoor, Sarhan Mohammed, Arwa Al-Adhreai, Selahaddin Güner, Mohammed ALSaeedy","doi":"10.1007/s12035-026-06173-4","DOIUrl":"10.1007/s12035-026-06173-4","url":null,"abstract":"<p><p>Mast cells (MCs) are versatile immune cells that play a key role in neuroimmune interactions due to their strategic localization in barrier tissues and perineuronal sites, including the meninges, choroid plexus, thalamus, hypothalamus, and hippocampus within the central nervous system (CNS), as well as peripheral sites such as the skin, gastrointestinal tract, and dorsal root ganglia. They rapidly release stored and newly synthesized mediators, including histamine, tryptase, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), substance P, and prostaglandins, which regulate nerve signaling, vascular function, and inflammation. This review presents a framework integrating MC differentiation with distinct CNS microenvironments to explain their neuroprotective and toxic roles. The anatomical and molecular basis of MC-neuron interaction is discussed, with emphasis on bidirectional signaling via neuropeptides, neurotransmitters, and cytokines. MC functions in the CNS are highlighted, including neuroprotection through synaptic plasticity and BBB integrity under homeostatic conditions, as well as neurotoxicity, where aberrant activation promotes BBB breakdown, microglial priming, and neuroinflammatory cascades. Furthermore, the roles in which mast cell dysfunction is implicated in neurodegenerative and psychiatric disorders are examined, including Alzheimer's disease (AD), where amyloid-β triggers MC degranulation, Parkinson's disease (PD), where α-synuclein induces MC activation, multiple sclerosis (MS), autism, anxiety, and depression, as well as peripheral neuroimmune conditions affecting the skin, gut-brain axis, and pain. Current and emerging mast cell-targeted therapies, including stabilizers, histamine receptor blockers, tryptase inhibitors, and anti-IgE biologics, are discussed, along with future challenges in mast cell-based neuroimmunological treatment.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Determining Acute-Phase Biomarkers for Mild Traumatic Brain Injury Through Exploratory Data Analysis: A Preliminary Report.","authors":"João Luís Vieira Monteiro de Barros, Maíra Glória de Freitas Cardoso, Danielle Emely de Souza Almeida, Agnes Stéphanie da Silva, Caroline Amaral Machado, Bruna da Silva Oliveira, Isabella Alves Teixeira de Abreu, Patrícia Fernandes Fontes, Natalia Pessoa Rocha, Vinicius Sousa Pietra Pedroso, Rodrigo Moreira Faleiro, Érica Leandro Marciano Vieira, Antônio Lúcio Teixeira, Leonardo Cruz de Souza, Rafael Alves Bonfim de Queiroz, Aline Silva de Miranda","doi":"10.1007/s12035-026-06130-1","DOIUrl":"10.1007/s12035-026-06130-1","url":null,"abstract":"<p><p>The purpose of this study is to identify acute-phase serum biomarkers for mild traumatic brain injury (mTBI) within 24 h of trauma and evaluate their discriminatory value versus orthopedic trauma and healthy status using a leakage-safe machine-learning framework. We enrolled 60 patients with computed tomography (CT)-negative mTBI (World Health Organization [WHO] criteria; Glasgow Coma Scale [GCS] 13-15; age 18-59) within 24 h of injury, 17 orthopedic injury controls, and 24 healthy controls without mTBI in the prior 5 years. Fifty-nine serum biomarkers were quantified by Luminex®. The group comparisons used ANOVA or Kruskal-Wallis tests with corrected post hoc contrasts. Random Forest models were trained under leakage-safe nested cross-validation (outer 5-fold; inner 3-fold) with biomarker-only and biomarker-plus-demographics feature sets. SHAP values were computed on held-out folds and stability was assessed across resamples. Twenty-three biomarkers differed across groups after Bonferroni correction for post hoc comparisons (BDNF, EGF, Fracktalkine, G-CSF, GRO, IL15, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-9, LIGHT, MMP-9, MPO, NCAM, NRG1-β1, S100B, TGF- α, VEGF A, sICAM-1). In nested cross-validation, three-class balanced accuracy ranged ~0.48-0.70, and mTBI one-vs-rest receiver operating characteristic area under the curve (ROC-AUC) frequently exceeded 0.85; Control vs mTBI classification achieved balanced accuracy ~0.70-0.90 with precision-recall area under the curve (PR-AUC) consistently >0.82. Sex and age added minimal incremental value. Stable SHAP contributors (top-5 in ≥4/5 folds) were LIGHT, IL-5, sCD40L, MMP-9, EGF, and fractalkine. Acute mTBI is associated with a reproducible serum signature spanning inflammatory, vascular, and growth-factor pathways.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13614984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Interplay of Metabolic Dysfunction, Neuroinflammation, and Mitochondrial Dysfunction in Balance Impairment: Insights from Type 2 Diabetes Mellitus and Alzheimer's Disease.","authors":"Sodiq Fakorede, Olubodun Michael Lateef, Augustine Lishilinimye Udefa, Abayomi Oyeyemi Ajagbe, Sharmistha Roy, Priscilla Onaopemipo Akosile, Taiwo Ayomide Awobona, Godson Emeka Anyanwu","doi":"10.1007/s12035-026-06237-5","DOIUrl":"10.1007/s12035-026-06237-5","url":null,"abstract":"<p><p>Balance impairment and postural instability represent critical challenges for the aging population, serving as primary precursors to falls and functional decline in individuals with Type 2 Diabetes Mellitus. While traditional clinical models have largely separated these conditions, attributing balance loss in T2DM to peripheral neuropathy and in AD to central cortical atrophy, mounting evidence suggests a convergence of multi-system impairments driven by a shared central pathophysiology. This narrative review proposes an integrative framework centered on a vicious, self-reinforcing cycle involving metabolic dysfunction, chronic neuroinflammation, and mitochondrial failure as the core mechanistic link driving balance impairment. We detail how systemic and cerebral insulin resistance, coupled with glucotoxicity, trigger the activation of the NLRP3 inflammasome and the subsequent release of pro-inflammatory cytokines. This inflammatory environment exacerbates mitochondrial bioenergetic failure and oxidative stress, selectively targeting high-energy motor circuits such as the striatum and basal ganglia while simultaneously contributing to musculoskeletal sarcopenia and peripheral nerve demyelination. By synthesizing the intricate interplay between these molecular pathways, this review moves beyond disease-specific silos to offer a novel perspective on the shared pathophysiology of postural instability. Furthermore, we explore the therapeutic potential of metabolic modulators, such as GLP-1 receptor agonists, and mitochondrial-targeted antioxidants, alongside multimodal rehabilitation strategies. Ultimately, this unified model provides a foundation for developing precision-based interventions to mitigate fall risk and preserve functional independence in vulnerable aging populations.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Neuroprotective Responses to Achyrocline satureioides Extract in Caenorhabditis elegans: Modulation of Conserved FOXO/NRF2 Pathways and Resistance to Neurotoxic Insults.","authors":"Péterson Alves Santos, Eduardo Mariano de Andrade, Ionara Rodrigues Siqueira, Patrícia Pereira","doi":"10.1007/s12035-026-06212-0","DOIUrl":"10.1007/s12035-026-06212-0","url":null,"abstract":"<p><p>Achyrocline satureioides is widely consumed as an herbal infusion in South America; however, the toxicological profile of its aqueous extract (ASAE), particularly under conditions of neurotoxic stress, remains incompletely characterized. In the present study, we investigated the safety profile of ASAE and its capacity to modulate chemically induced neurotoxicity by integrating in silico toxicological predictions with in vivo assays in Caenorhabditis elegans. Wild-type and mutant strains deficient in key stress-response regulators (daf-2, daf-16, and skn-1) were exposed to ASAE (10-50 mg/mL). Toxicological and neurofunctional endpoints included survival under methylmercury (MeHg) exposure, PTZ-induced paralysis, locomotor performance, lipofuscin accumulation as a biomarker of oxidative damage, and activation of stress-responsive signaling pathways. Chronic ASAE exposure did not induce developmental toxicity or reduce lifespan at the tested concentrations. Notably, ASAE pre-exposure was associated with reduced behavioral deficits induced by MeHg and delayed PTZ-induced paralysis, indicating reduced susceptibility to chemically induced neurotoxic insults. Mechanistic analyses suggested that these findings are consistent with the involvement of conserved stress-response pathways involving daf-16 and skn-1, regulators functionally analogous to mammalian FOXO and NRF2 signaling. Consistent with these findings, computational toxicology predicted low systemic toxicity for major ASAE constituents and limited interaction with toxicity-related biomarkers. Collectively, these results indicate that ASAE exhibits a favorable toxicological profile and modulates conserved molecular pathways that enhance resilience to neurotoxic stress in C. elegans.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisiting Alzheimer's Disease Through the Somatostatin-Mitochondria Axis.","authors":"Kai Liu, Xi-Yu Zhang, Hong-Bo Qiu, Chen-Qi Su, Shao-Yun Wang, Zi-Jun Pei, Run-Hao Jin, Yan-Hua Bing","doi":"10.1007/s12035-026-06221-z","DOIUrl":"10.1007/s12035-026-06221-z","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and pathological hallmarks such as amyloid-beta (Aβ) deposition and tau hyperphosphorylation. Increasing evidence identifies mitochondrial dysfunction as an early and central driver of AD pathogenesis, contributing to impaired bioenergetics, oxidative stress, disrupted calcium homeostasis, and synaptic failure. Notably, somatostatin (SST), a neuropeptide significantly reduced in AD brains, has emerged as a candidate regulator of neuronal metabolism and mitochondrial homeostasis. In this review, we propose a conceptual and testable framework linking reduced SST signaling to mitochondrial dysfunction in AD. Current evidence most directly supports effects of SST signaling on neuronal excitability and calcium homeostasis, whereas direct evidence linking SST or individual SSTR subtypes-particularly SSTR2 and SSTR4-to mitochondrial bioenergetics, mitophagy, cristae organization, and mitochondrial dynamics remains limited and is discussed here largely at the level of plausible, testable hypotheses. Downstream signaling pathways, including Gi-coupled inhibition of cAMP/PKA and modulation of PI3K/Akt, have established roles in neuronal signaling and are discussed here in relation to their potential, but not yet directly demonstrated, contributions to mitochondrial bioenergetics, redox balance, calcium handling, mitophagy, and mitochondrial dynamics. Disruption of these processes may plausibly contribute to a self-amplifying cycle involving Aβ accumulation, tau pathology, and synaptic dysfunction, although this cycle has not been directly demonstrated for SST signaling specifically. Collectively, the SST-mitochondria axis represents a conceptual and testable framework that may help explain aspects of AD pathogenesis, pending direct mechanistic validation, offering promising therapeutic opportunities beyond conventional amyloid- and tau-centric approaches. Future research should focus on receptor subtype-specific mechanisms, mitophagy modulation, and mitochondrial calcium regulation to advance translational applications.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CircBRWD1 Drives Atherosclerotic Plaque Progression by Modulating Macrophage Inflammatory Responses Through miR-141-5p/HMGB1/NF-κB Signaling.","authors":"Cheng Wen, Zhi Fang, Yushuang Ruan, Houying Mu, Zikang Dong, Enxiang Tao, Yuanpeng Xia","doi":"10.1007/s12035-026-06196-x","DOIUrl":"10.1007/s12035-026-06196-x","url":null,"abstract":"<p><p>Atherosclerosis is a chronic inflammatory vascular disease. Circular RNAs (circRNAs) have emerged as important regulators of inflammatory processes, but their roles and regulatory mechanisms in atherosclerosis remain incompletely understood. This study aimed to investigate the role of circBRWD1 in atherosclerosis and its involvement in macrophage inflammatory responses. The expression and cellular localization of circBRWD1 were examined in high fat diet (HFD)-fed Apolipoprotein E knockout (ApoE^-/-) mice using qRT-PCR, fluorescence in situ hybridization (FISH) and immunofluorescence. The effects of AAV-mediated circBRWD1 knockdown on atherosclerotic lesions and plaque-associated inflammatory responses were evaluated in ApoE^-/- mice. The regulatory effects of circBRWD1 on macrophage inflammatory responses were further investigated in RAW264.7 macrophages using qRT-PCR, western blotting, ELISA and flow cytometry. The interaction between circBRWD1 and miR-141-5p and the regulation of HMGB1 by miR-141-5p were investigated using bioinformatic prediction, RNA pull-down, RNA immunoprecipitation, FISH, dual-luciferase reporter assays and functional rescue experiments. CircBRWD1 expression increased during atherosclerotic plaque development and was predominantly detected in macrophage-rich regions of advanced lesions. AAV-mediated circBRWD1 knockdown reduced aortic lesion size, plaque lipid accumulation, necrotic core area, TUNEL-positive signals and plaque-associated inflammatory markers in ApoE^-/- mice. In RAW264.7 macrophages, circBRWD1 preferentially modulated pro-inflammatory responses, including iNOS, CD86, and pro-inflammatory cytokine expression. Mechanistically, circBRWD1 interacted with miR-141-5p and modulated miR-141-5p-mediated regulation of HMGB1 and downstream NF-κB-associated inflammatory signaling. These findings identify circBRWD1 as a potential regulator of atherosclerotic plaque progression and macrophage inflammatory responses, and support the involvement of the miR-141-5p/HMGB1/NF-κB regulatory relationship in these effects. circBRWD1 may therefore represent a potential target for modulating plaque-associated inflammation in atherosclerosis.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149031004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The SLC7A11 Thermostat: A Molecular Signaling Switch Between Ferroptosis and Disulfidptosis in Neurodegenerative Disease.","authors":"Mohammed Zayed, Maha Mahmoud, Ahmed Massoud, Renad Darwish, Byung-Hoon Jeong","doi":"10.1007/s12035-026-06219-7","DOIUrl":"10.1007/s12035-026-06219-7","url":null,"abstract":"<p><p>Neurodegenerative diseases are characterized by a metabolic paradox, a balance regulated at the molecular level by a narrow set of redox-sensitive signaling checkpoints. The cystine/glutamate antiporter SLC7A11 plays a central role in this challenge. Traditionally recognized as an antioxidant guardian that prevents ferroptosis through NRF2-KEAP1-driven glutathione synthesis, SLC7A11 can become a burden under metabolic stress. Under glucose restriction or mitochondrial dysfunction, impaired NADPH regeneration prevents cells from reducing imported cystine, leading to disulfide stress in cytoskeletal actin-binding proteins and a novel form of regulated cell death called disulfidptosis. We suggest that neural cell fate and intercellular redox support depend not only on the presence of SLC7A11 activity but also on its specific calibration in each cell type, taking into account cystine availability, glutamate management, and NADPH regeneration. Since baseline system Xc⁻ activity in the CNS is primarily observed in astrocytes and microglia, this regulatory mechanism may operate both within individual cells and across cell types via the astrocyte-neuron metabolic network. Within this proposed framework, insufficient SLC7A11 activity may increase ferroptotic susceptibility, whereas sustained cystine uptake under severe NADPH limitation may create conditions permissive for disulfidptosis. In Alzheimer's disease, chronic cerebral glucose hypometabolism might lead to disulfide stress in neural cells with high SLC7A11 levels, although the typical disulfidptosis process has not yet been confirmed in vivo. We argue that traditional antioxidant supplements or SLC7A11 modulation are unlikely to succeed without understanding this dual-risk profile at the level of molecular pathways. We propose shifting toward precise adjustment via biomarker-guided redox modulators and metabolic priming to enhance NADPH reserves. By examining SLC7A11 as a dynamic molecular regulator, this review offers a hypothesis-generating framework that may help resolve conflicting findings and inform the development of focused neuroprotective approaches relevant to the molecular neurobiology of neurodegenerative disease.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149031051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resveratrol Ameliorates Brain Functions During Gestation in Mancozeb-Low-Dose-Induced Brain Disorders via Mitigating Inflammation, Lipid Peroxidation, Mitochondrial Dysfunction, DNA Damage, Cell Death, and Histopathological Alterations.","authors":"Rana M El-Sawah, Amoura M Abou-El-Naga, Nermeen E Ashry, Heba A El-Ghaweet","doi":"10.1007/s12035-026-06167-2","DOIUrl":"10.1007/s12035-026-06167-2","url":null,"abstract":"<p><p>Worldwide, many old and young people suffer from neurodegenerative brain disorders. Continuous exposure to mancozeb (MNZ), a fungicide extensively used worldwide on a wide range of crops, is a serious threat to public health because of inducing neuroinflammation and oxidative stress. Resveratrol (RES) is a natural polyphenol with antioxidant and anti-inflammatory effects. This study evaluated the neuroprotective potential of RES against MNZ low-dose-induced brain damage during gestation and elucidated its underlying mechanisms. Thirty-two pregnant Wistar rats were randomly allocated into four groups (n = 8): control, RES-treated rats (100 mg/kg/day, intraperitoneal injection), MNZ-treated rats (100 mg/kg/day, oral), and RES + MNZ-treated rats (100 mg/kg/day intraperitoneal before 100 mg/kg/day MNZ oral). Treatments were administered daily from gestational day (GD) 1 to GD 20. On GD 20, brain samples were collected for biochemical, DNA integrity, morphometric, histopathological, and immunohistochemical assays. Gestational MNZ exposure induced neuroinflammation, lipid peroxidation, reduced CAT activity, and triggered GFAP accumulation, resulting in astrogliosis in the cerebrum and hippocampus. Furthermore, MNZ disrupted mitochondrial apoptosis regulatory proteins, increased DNA damage in maternal and fetal brain cells, induced cerebral and hippocampal neurodegeneration, and reduced cortical thickness while increasing the hippocampal stratum lucidum thickness. Remarkably, pretreatment with RES protected the maternal and fetal brains, preserving cerebral and hippocampal-dependent brain functions through suppressing lipid peroxidation, inflammation, mitochondrial-mediated apoptosis, DNA damage, and histopathological changes. In conclusion, RES demonstrates a potent prophylactic neuroprotective efficacy during gestation against MNZ-induced neurotoxicity, suggesting its potential value as a preventive dietary agent against environmental toxin-mediated brain disorders.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CXCR4 Coordinates Long-Term Olfactory Epithelial Regeneration and Cellular Stress Response After Injury.","authors":"Katja Senf, André Dietz, Julia Karius, Eva M Neuhaus","doi":"10.1007/s12035-026-06215-x","DOIUrl":"10.1007/s12035-026-06215-x","url":null,"abstract":"<p><p>During development, the chemokine receptor CXCR4 directs axon guidance, but it is not known if CXCR4 regulates axon targeting in the adult organism as well. We utilized the remarkable feature of the olfactory epithelium to replace damaged neurons throughout life to understand the role of CXCR4 in adult neurogenesis. Through targeting Cxcr4 in horizontal basal stem cells of the olfactory epithelium, we investigated the role of CXCR4 during injury-induced neurogenesis in adult mice by a combination of RNA-seq analysis, bioinformatic methods, behavioral experiments, and microscopical approaches. Conditional knockout mice lacking Cxcr4 initially displayed enhanced regeneration after injury of the olfactory system, resulting in increased numbers of sensory neurons and enhanced sense of smell. Moreover, we found that absence of CXCR4 alters expression of axon guidance proteins. Despite accelerated early neurogenesis, loss of CXCR4 ultimately impaired the reconstruction of the dorsomedial olfactory epithelium, leading to disrupted glomerular organization and reduced avoidance responses to aversive odors. Transcriptomic analysis revealed altered stress response pathways, suggesting impaired cellular adaptation in Cxcr4-cKO mice during regenerative repair. An increased level of ER stress in horizontal basal cells led to instability of the basal lamina, respiratory metaplasia in the dorsomedial part of the olfactory epithelium, and Bowman gland regeneration failure.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Convergent Astrocytic Failure in Parkinson's Disease: A System-Level Model of Pathogenesis and Treatment.","authors":"Ahmed M Abdelaziz, Mohamed N Fawzy, Mustafa M Shokr","doi":"10.1007/s12035-026-06177-0","DOIUrl":"10.1007/s12035-026-06177-0","url":null,"abstract":"<p><p>A paradigm shift from a purely neurodegenerative disorder to a multicellular failure of the neuroglial unit has fundamentally redefined Parkinson's disease (PD). This review synthesizes compelling evidence that positions astrocyte dysfunction, or astrocytopathy, as a central and active driver of pathogenesis, extending far beyond a passive bystander role. We delineate how pathological α-synuclein triggers a vicious cycle of astrocytic failure, encompassing impaired proteostasis via ubiquitin-proteasome and autophagy-lysosomal pathways, glymphatic system collapse due to aquaporin-4 (AQP4) depolarization, and chronic neuroinflammation driven by microglial crosstalk and NLRP3 inflammasome activation. This core triad is exacerbated by critical deficits in metabolic support, including disruption of the astrocyte-neuron lactate shuttle, aberrant lipid droplet metabolism, and failure in mitochondrial transfer. Furthermore, we integrate emerging systemic axes, demonstrating how peripheral gut dysbiosis, via the microbiota-gut-astrocyte (MGA) axis, and central circadian rhythm disruption converge to amplify central glial pathology. Critically, the present reframing unveils novel, cell-type-specific therapeutic avenues. We evaluate strategies to restore neuroprotection by targeting AQP4 polarization, modulating GLP-1 receptor signaling to mitigate inflammation, employing senolytics to clear dysfunctional glia, and utilizing gene therapy to engineer astrocytes as trophic bio-factories. By deconstructing PD as a disorder of astrocyte-neuron crosstalk, this review provides a roadmap for next-generation, disease-modifying therapies aimed at rescuing glial homeostasis to halt progression, moving beyond symptomatic dopamine replacement to address the core pathophysiology.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}