Pub Date : 2026-01-24DOI: 10.1016/j.nbd.2026.107281
Deborah Pré, Christian Cazares, Alexander T Wooten, Haowen Zhou, Isabel Onofre, Ashley Neil, Todd Logan, Ruilong Hu, Jan H Lui, Bradley Voytek, Anne G Bang
Dynamically coupled neural networks are fundamental to human cognition and behavior and are disrupted in neurodevelopmental disorders. The formation and dissolution of functional networks is thought to be driven by synchronized oscillatory bursts across large populations of neurons. The mechanisms driving the emergence of these rhythms, known as oscillogenesis, are not well understood, particularly in the human brain. Using multi-electrode arrays, we investigated oscillogenesis in human induced pluripotent stem cell 2D neural cultures at different developmental stages and under pharmacological challenges. We found that cultures exhibited nested oscillations that were reduced by GABAA receptor blockade and emerged earlier when the proportion of GABAergic neurons was increased. Pharmacological manipulations of voltage-gated potassium channels and cholinergic receptors modulated the pattern of nested oscillations. These results reveal the capacity of these 2D cultures to model oscillogenesis, and underscore the need for their continued refinement, paving the way for linking systems-level neural networks to human cognition and disease.
{"title":"Pharmacological manipulation of nested oscillations in human iPSC-derived 2D neuronal networks.","authors":"Deborah Pré, Christian Cazares, Alexander T Wooten, Haowen Zhou, Isabel Onofre, Ashley Neil, Todd Logan, Ruilong Hu, Jan H Lui, Bradley Voytek, Anne G Bang","doi":"10.1016/j.nbd.2026.107281","DOIUrl":"10.1016/j.nbd.2026.107281","url":null,"abstract":"<p><p>Dynamically coupled neural networks are fundamental to human cognition and behavior and are disrupted in neurodevelopmental disorders. The formation and dissolution of functional networks is thought to be driven by synchronized oscillatory bursts across large populations of neurons. The mechanisms driving the emergence of these rhythms, known as oscillogenesis, are not well understood, particularly in the human brain. Using multi-electrode arrays, we investigated oscillogenesis in human induced pluripotent stem cell 2D neural cultures at different developmental stages and under pharmacological challenges. We found that cultures exhibited nested oscillations that were reduced by GABAA receptor blockade and emerged earlier when the proportion of GABAergic neurons was increased. Pharmacological manipulations of voltage-gated potassium channels and cholinergic receptors modulated the pattern of nested oscillations. These results reveal the capacity of these 2D cultures to model oscillogenesis, and underscore the need for their continued refinement, paving the way for linking systems-level neural networks to human cognition and disease.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107281"},"PeriodicalIF":5.6,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053176","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}
Pub Date : 2026-01-22DOI: 10.1016/j.nbd.2026.107284
Leticia Villalba-Benito , Justine Mathoux , Theresa Auer , Kaushik Narasimhan , Ruth Colbert , James P. Reynolds , Elizabeth Brindley , Aasia Batool , Thomas D.M. Hill , Mairead Diviney , Morten T. VenØ , Marco Prinz , Niamh M.C. Connolly , Dearbhaile Dooley , David C. Henshall , Gary P. Brennan
Small RNAs including microRNAs (miRNAs) and tRNA fragments (tRFs) are key post-transcriptional regulators of gene expression in temporal lobe epilepsy (TLE), but the cellular origin of these changes is often unclear. Here, we dissected the cell-type specific small RNA landscape, focussing on miRNA and tRFs, during epileptogenesis and in chronic epilepsy by profiling the RNA-induced silencing complex (RISC) using novel, transgenic mice with inducible expression of a FLAG-tagged Argonaute 2 protein driven specifically in neurons (Thy1-Ago2) or microglia (Cx3cr1-Ago2). We induced epilepsy in male mice via intra-amygdala microinjection of kainic acid and tracked miRNA expression over time in the hippocampus. Microglia and neurons displayed distinct and largely non-overlapping small RNA profiles across disease. Shortly following the epileptogenic insult, we detected a rapid microglial miRNA and tRF response which was sustained in chronic stages of the disease whereas small RNA changes in neurons displayed a delayed but sustained wave of unique changes as the disease progressed. Interestingly, our data reveals selective loading and incorporation of miRNAs into Ago2/RISC complexes, independent of overall abundance, in a cell- and disease-stage specific manner as well as differential processing of tRNAs in microglia compared to neurons. Additionally we found that certain epilepsy-associated miRNAs, previously considered ubiquitous, display dysregulation in multiple cell types while exhibiting cell-specific activity. Together our results demonstrate the cell-specific small RNA responses and functions to epileptogenic insults and shed further light on the complexity of post-transcriptional gene dysregulation in TLE. The findings indicate the potential advantages of targeted, cell-specific therapeutic strategies to effectively modulate miRNA pathways in epilepsy.
{"title":"Distinct Argonaute2-associated small RNA profiles in microglia and neurons drive cell-specific responses in a mouse model of temporal lobe epilepsy","authors":"Leticia Villalba-Benito , Justine Mathoux , Theresa Auer , Kaushik Narasimhan , Ruth Colbert , James P. Reynolds , Elizabeth Brindley , Aasia Batool , Thomas D.M. Hill , Mairead Diviney , Morten T. VenØ , Marco Prinz , Niamh M.C. Connolly , Dearbhaile Dooley , David C. Henshall , Gary P. Brennan","doi":"10.1016/j.nbd.2026.107284","DOIUrl":"10.1016/j.nbd.2026.107284","url":null,"abstract":"<div><div>Small RNAs including microRNAs (miRNAs) and tRNA fragments (tRFs) are key post-transcriptional regulators of gene expression in temporal lobe epilepsy (TLE), but the cellular origin of these changes is often unclear. Here, we dissected the cell-type specific small RNA landscape, focussing on miRNA and tRFs, during epileptogenesis and in chronic epilepsy by profiling the RNA-induced silencing complex (RISC) using novel, transgenic mice with inducible expression of a FLAG-tagged Argonaute 2 protein driven specifically in neurons (Thy1-Ago2) or microglia (Cx3cr1-Ago2). We induced epilepsy in male mice via intra-amygdala microinjection of kainic acid and tracked miRNA expression over time in the hippocampus. Microglia and neurons displayed distinct and largely non-overlapping small RNA profiles across disease. Shortly following the epileptogenic insult, we detected a rapid microglial miRNA and tRF response which was sustained in chronic stages of the disease whereas small RNA changes in neurons displayed a delayed but sustained wave of unique changes as the disease progressed. Interestingly, our data reveals selective loading and incorporation of miRNAs into Ago2/RISC complexes, independent of overall abundance, in a cell- and disease-stage specific manner as well as differential processing of tRNAs in microglia compared to neurons. Additionally we found that certain epilepsy-associated miRNAs, previously considered ubiquitous, display dysregulation in multiple cell types while exhibiting cell-specific activity. Together our results demonstrate the cell-specific small RNA responses and functions to epileptogenic insults and shed further light on the complexity of post-transcriptional gene dysregulation in TLE. The findings indicate the potential advantages of targeted, cell-specific therapeutic strategies to effectively modulate miRNA pathways in epilepsy.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107284"},"PeriodicalIF":5.6,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043325","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}
Pub Date : 2026-01-21DOI: 10.1016/j.nbd.2026.107282
Danielle Santana-Coelho , Rafael dos Santos de Bessa , Rodrigo Neves Romcy-Pereira , Miguel A. de la Flor , Jason C. O'Connor
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms that may include deficits in communication, social challenges, and repetitive/stereotyped behavior. The etiology of ASD is not well defined, but both genetic and environmental risk factors have been identified. In animal models, prenatal maternal immune activation precipitates the development of a behavioral phenotype resembling ASD, but the mechanisms by which this occurs are not fully understood. Inflammation can upregulate the kynurenine pathway metabolism through the enzyme indoleamine 2,3-dioxygenase-1 (IDO). Increased levels of kynurenines during development can have deleterious consequences leading to behavioral deficits in adulthood. We sought to determine whether the kynurenine pathway plays a pathogenic role in the development of an ASD-like phenotype using a well-characterized mouse model of maternal immune activation (MIA). Multiparous IDO null (IDO−/−) or C57BL/6 J wild-type dams were administered the viral mimetic polynosinic:polycytidylic acid (Poly IC) at gestational day 12.5. A similar immune response to Poly IC occurred in the maternal plasma and placenta of both genotypes, while kynurenine metabolism was only increased in the fetal tissue of WT mice exposed to Poly IC challenge. Interestingly, N-methyl-d-aspartate (NMDA) receptor subunit expression was reduced in the fetal brains of male WT, but not IDO−/−, after MIA with Poly IC. Here, we used machine-learning as an advanced method to evaluate ultrasonic vocalizations. Offspring exposed to prenatal MIA exhibited fewer and less complex ultrasonic vocalizations along with diminished social preference; however, MIA-induced repetitive/stereotyped behaviors were only present in WT mice. Taken together, our data indicate that fetal IDO1-dependent kynurenine metabolism mediates distinct components of the MIA-induced ASD-like phenotype in male mice, which may be related to alterations in the expression of NMDAR subunits during neurodevelopment.
{"title":"The role of the kynurenine pathway in the pathophysiology of autism-like phenotype induced by maternal inflammation in male mice","authors":"Danielle Santana-Coelho , Rafael dos Santos de Bessa , Rodrigo Neves Romcy-Pereira , Miguel A. de la Flor , Jason C. O'Connor","doi":"10.1016/j.nbd.2026.107282","DOIUrl":"10.1016/j.nbd.2026.107282","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms that may include deficits in communication, social challenges, and repetitive/stereotyped behavior. The etiology of ASD is not well defined, but both genetic and environmental risk factors have been identified. In animal models, prenatal maternal immune activation precipitates the development of a behavioral phenotype resembling ASD, but the mechanisms by which this occurs are not fully understood. Inflammation can upregulate the kynurenine pathway metabolism through the enzyme indoleamine 2,3-dioxygenase-1 (IDO). Increased levels of kynurenines during development can have deleterious consequences leading to behavioral deficits in adulthood. We sought to determine whether the kynurenine pathway plays a pathogenic role in the development of an ASD-like phenotype using a well-characterized mouse model of maternal immune activation (MIA). Multiparous IDO null (IDO−/−) or C57BL/6 J wild-type dams were administered the viral mimetic polynosinic:polycytidylic acid (Poly IC) at gestational day 12.5. A similar immune response to Poly IC occurred in the maternal plasma and placenta of both genotypes, while kynurenine metabolism was only increased in the fetal tissue of WT mice exposed to Poly IC challenge. Interestingly, <em>N</em>-methyl-<span>d</span>-aspartate (NMDA) receptor subunit expression was reduced in the fetal brains of male WT, but not IDO−/−, after MIA with Poly IC. Here, we used machine-learning as an advanced method to evaluate ultrasonic vocalizations. Offspring exposed to prenatal MIA exhibited fewer and less complex ultrasonic vocalizations along with diminished social preference; however, MIA-induced repetitive/stereotyped behaviors were only present in WT mice. Taken together, our data indicate that fetal IDO1-dependent kynurenine metabolism mediates distinct components of the MIA-induced ASD-like phenotype in male mice, which may be related to alterations in the expression of NMDAR subunits during neurodevelopment.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107282"},"PeriodicalIF":5.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041479","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}
Pub Date : 2026-01-20DOI: 10.1016/j.nbd.2026.107278
Hongguo Li, Yuchen Zhu, Peijie Liu, Siqi Song, Xiping Zhang, Chenxu Liu, Minghui Hu, Yao Zhang, Chaojie Wang, Yushi Hu
<div><div>The high global prevalence of anxiety disorders, coupled with the limitations of existing treatments, constitutes a severe public health challenge. Chronic stress, as a core environmental trigger, has garnered increasing attention for its mechanism of mediating brain-derived neurotrophic factor (BDNF) imbalance through neuroinflammation. BDNF dysregulation may contribute to anxiety disorders, particularly in subtypes with heightened neuroinflammation. The objective of this review is to comprehensively and methodically explores the potential role of the “M1-like microglia-A1-like astrocyte axis (M1-A1 axis)” in linking chronic stress to BDNF dysregulation in anxiety disorders, and to provide a theoretical basis for intervention strategies targeting this axis. By synthesizing recent relevant clinical and preclinical evidence, this review integrates evidence from molecular to systems levels, focusing on the activation mechanisms of neuroinflammation under chronic stress, the crosstalk between glial cells, and their regulatory network on BDNF. Chronic stress is associated with peripheral and central cascades through hypothalamic-pituitary-adrenal (HPA) axis activation and gut microbiota disruption. Within the central nervous system (CNS), stress induces microglial polarization toward the pro-inflammatory microglial subpopulations (hereinafter referred to as M1-like microglia). The signals released by M1-like microglia, such as Interleukin-1 alpha (IL-1α), Tumor Necrosis Factor-alpha (TNF-α), and Complement Component 1q (C1q) (ITC), drive astrocytes to transform into the neurotoxic astrocyte states (hereinafter referred to as A1-like astrocyte), forming the “M1-A1 axis”. This axis contributes to BDNF dysregulation through the following mechanisms: (1) Release of pro-inflammatory cytokines inhibits BDNF transcription and translation; (2) Induction of astrocytic lactate metabolism disruption, which impairs neuronal energy supply and acidifies the microenvironment, further amplifying inflammation and affecting BDNF expression; (3) Compromise of the blood-brain barrier(<em>BBB</em>)enables peripheral immune cells to penetrate into the CNS, and these cells work in synergy with central glial cells to amplify inflammation. The reduction in BDNF and the imbalance in the ratio of its precursor to mature form ultimately lead to impaired synaptic plasticity in brain regions like the hippocampus (HIP) and amygdala, precipitating anxiety-like behaviors. Existing pharmacological interventions are inadequate to reverse this pathological process. The M1-A1 axis may serve as a key node linking chronic stress to BDNF dysregulation and anxiety disorders. Targeting the phenotypic transformation of glial cells, repairing the BBB, or modulating glial cell metabolism (e.g., lactate shuttle) may represent potential strategies<!--> <!--> requiring further validation. Future research should focus on the spatiotemporal dynamics of this axis and its clinical translatio
{"title":"The M1-like microglia-A1-like astrocyte Axis: A central hub linking BDNF dysregulation in chronic stress to anxiety disorders","authors":"Hongguo Li, Yuchen Zhu, Peijie Liu, Siqi Song, Xiping Zhang, Chenxu Liu, Minghui Hu, Yao Zhang, Chaojie Wang, Yushi Hu","doi":"10.1016/j.nbd.2026.107278","DOIUrl":"10.1016/j.nbd.2026.107278","url":null,"abstract":"<div><div>The high global prevalence of anxiety disorders, coupled with the limitations of existing treatments, constitutes a severe public health challenge. Chronic stress, as a core environmental trigger, has garnered increasing attention for its mechanism of mediating brain-derived neurotrophic factor (BDNF) imbalance through neuroinflammation. BDNF dysregulation may contribute to anxiety disorders, particularly in subtypes with heightened neuroinflammation. The objective of this review is to comprehensively and methodically explores the potential role of the “M1-like microglia-A1-like astrocyte axis (M1-A1 axis)” in linking chronic stress to BDNF dysregulation in anxiety disorders, and to provide a theoretical basis for intervention strategies targeting this axis. By synthesizing recent relevant clinical and preclinical evidence, this review integrates evidence from molecular to systems levels, focusing on the activation mechanisms of neuroinflammation under chronic stress, the crosstalk between glial cells, and their regulatory network on BDNF. Chronic stress is associated with peripheral and central cascades through hypothalamic-pituitary-adrenal (HPA) axis activation and gut microbiota disruption. Within the central nervous system (CNS), stress induces microglial polarization toward the pro-inflammatory microglial subpopulations (hereinafter referred to as M1-like microglia). The signals released by M1-like microglia, such as Interleukin-1 alpha (IL-1α), Tumor Necrosis Factor-alpha (TNF-α), and Complement Component 1q (C1q) (ITC), drive astrocytes to transform into the neurotoxic astrocyte states (hereinafter referred to as A1-like astrocyte), forming the “M1-A1 axis”. This axis contributes to BDNF dysregulation through the following mechanisms: (1) Release of pro-inflammatory cytokines inhibits BDNF transcription and translation; (2) Induction of astrocytic lactate metabolism disruption, which impairs neuronal energy supply and acidifies the microenvironment, further amplifying inflammation and affecting BDNF expression; (3) Compromise of the blood-brain barrier(<em>BBB</em>)enables peripheral immune cells to penetrate into the CNS, and these cells work in synergy with central glial cells to amplify inflammation. The reduction in BDNF and the imbalance in the ratio of its precursor to mature form ultimately lead to impaired synaptic plasticity in brain regions like the hippocampus (HIP) and amygdala, precipitating anxiety-like behaviors. Existing pharmacological interventions are inadequate to reverse this pathological process. The M1-A1 axis may serve as a key node linking chronic stress to BDNF dysregulation and anxiety disorders. Targeting the phenotypic transformation of glial cells, repairing the BBB, or modulating glial cell metabolism (e.g., lactate shuttle) may represent potential strategies<!--> <!--> requiring further validation. Future research should focus on the spatiotemporal dynamics of this axis and its clinical translatio","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107278"},"PeriodicalIF":5.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030433","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}
Pub Date : 2026-01-20DOI: 10.1016/j.nbd.2026.107279
Jiale Cai , Xiongbo Luo , Wenli Cui , Xinya Zheng , Shuyi Xu , Xinrui Ma , Ye He , Xianghai Wang , Jiasong Guo
Disruption of the blood-brain barrier (BBB) is an important cause of secondary injury following cerebral ischemia-reperfusion (I/R). Database analyses revealed RhoA upregulation in macrophages/microglia within I/R brain tissue; however, the role of macrophage/microglial RhoA in BBB disruption and I/R injury remains poorly understood. In this study, we verified that macrophage/microglial RhoA was significantly upregulated in I/R mice. Employing conditional knockout (cKO) mice, present study demonstrated that the macrophage/microglial RhoA deficiency exacerbates I/R injury, manifesting as enlarged infarct volumes, aggravated cerebral oedema and BBB leakage. Mechanistically, RhoA deficiency alters the secretory profile of macrophages/microglia, enhancing pro-inflammatory factors production in macrophages/microglia, which subsequently induces pyroptosis and apoptosis while downregulates tight junction proteins in endothelial cells via the NLRP3 pathway. Collectively, our findings revealed a novel macrophage/microglial-endothelial crosstalk mechanism whereby I/R-induced RhoA upregulation in macrophages/microglia serves to attenuate their pro-inflammatory polarization, thereby preserving BBB function through suppression of NLRP3-mediated pyroptosis and apoptosis in the endothelial cells. These findings may reshape the conventional view of RhoA inhibition therapy and pave the way for more precise, cell-targeted interventions in I/R brain injury.
{"title":"RhoA deletion in macrophages/microglia aggravates blood-brain barrier disruption after ischemic stroke reperfusion injury by promoting endothelial cell apoptosis and pyroptosis","authors":"Jiale Cai , Xiongbo Luo , Wenli Cui , Xinya Zheng , Shuyi Xu , Xinrui Ma , Ye He , Xianghai Wang , Jiasong Guo","doi":"10.1016/j.nbd.2026.107279","DOIUrl":"10.1016/j.nbd.2026.107279","url":null,"abstract":"<div><div>Disruption of the blood-brain barrier (BBB) is an important cause of secondary injury following cerebral ischemia-reperfusion (I/R). Database analyses revealed RhoA upregulation in macrophages/microglia within I/R brain tissue; however, the role of macrophage/microglial RhoA in BBB disruption and I/R injury remains poorly understood. In this study, we verified that macrophage/microglial RhoA was significantly upregulated in I/R mice. Employing conditional knockout (cKO) mice, present study demonstrated that the macrophage/microglial RhoA deficiency exacerbates I/R injury, manifesting as enlarged infarct volumes, aggravated cerebral oedema and BBB leakage. Mechanistically, RhoA deficiency alters the secretory profile of macrophages/microglia, enhancing pro-inflammatory factors production in macrophages/microglia, which subsequently induces pyroptosis and apoptosis while downregulates tight junction proteins in endothelial cells via the NLRP3 pathway. Collectively, our findings revealed a novel macrophage/microglial-endothelial crosstalk mechanism whereby I/R-induced RhoA upregulation in macrophages/microglia serves to attenuate their pro-inflammatory polarization, thereby preserving BBB function through suppression of NLRP3-mediated pyroptosis and apoptosis in the endothelial cells. These findings may reshape the conventional view of RhoA inhibition therapy and pave the way for more precise, cell-targeted interventions in I/R brain injury.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107279"},"PeriodicalIF":5.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030404","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}
Pub Date : 2026-01-20DOI: 10.1016/j.nbd.2026.107283
Jiaqin Jin , Qiuyu Cen , Huage Wang , Yin Xin , Jing Feng , Yanru Cui , JiaYu Li , Zilong You , Fangyuan Jing , Yang Yu , Yingbo Qiu , Rizhao Pang , Junyu Wang , Anren Zhang
Autophagy is a highly conserved lysosome-dependent degradation process that plays a crucial role in maintaining neuronal homeostasis and adaptation during stress by eliminating misfolded proteins, damaged organelles, and pathogens. Oxidative stress, triggered by an imbalance between reactive oxygen speciesreactive oxygen species:ROS (ROS) production and antioxidant defenses, contributes to disease pathogenesis through mechanisms such as lipid peroxidation, protein carbonylation, and mitochondrial DNA damage. Recent studies reveal that autophagy and oxidative stress interact via a dynamic bidirectional regulatory network to modulate neurodegenerative pathology: ROS activate autophagy by regulating signaling pathways and modifying autophagy-associated proteins, while moderate autophagic activity selectively clears ROS-generating components and activates antioxidant pathways. Dysregulation of autophagy or excessive ROS accumulation can disrupt this equilibrium, leading to cell death and disorders such as neurodegenerative diseases, cancer, and aging-related pathologies. They reciprocally serve as “pressure signals” and “clearance targets”, synergistically maintaining cellular homeostasis. This review synthesizes insights from current studies to systematically analyze the complex cross-talk between autophagy and oxidative stress in neurodegeneration and evaluates emerging therapeutic strategies targeting this interplay, including autophagy modulators, antioxidants, phytochemicals, and nanomaterials. These advancements offer novel perspectives for developing neuroprotective therapies through therapeutic modulation of the autophagy-oxidative stress axis. Finally, we summarize key challenges in the field and propose potential directions for future research.
{"title":"New perspective on neurodegenerative diseases: Focusing on the interaction between autophagy and oxidative stress and targeted strategies","authors":"Jiaqin Jin , Qiuyu Cen , Huage Wang , Yin Xin , Jing Feng , Yanru Cui , JiaYu Li , Zilong You , Fangyuan Jing , Yang Yu , Yingbo Qiu , Rizhao Pang , Junyu Wang , Anren Zhang","doi":"10.1016/j.nbd.2026.107283","DOIUrl":"10.1016/j.nbd.2026.107283","url":null,"abstract":"<div><div>Autophagy is a highly conserved lysosome-dependent degradation process that plays a crucial role in maintaining neuronal homeostasis and adaptation during stress by eliminating misfolded proteins, damaged organelles, and pathogens. Oxidative stress, triggered by an imbalance between reactive oxygen speciesreactive oxygen species:ROS (ROS) production and antioxidant defenses, contributes to disease pathogenesis through mechanisms such as lipid peroxidation, protein carbonylation, and mitochondrial DNA damage. Recent studies reveal that autophagy and oxidative stress interact via a dynamic bidirectional regulatory network to modulate neurodegenerative pathology: ROS activate autophagy by regulating signaling pathways and modifying autophagy-associated proteins, while moderate autophagic activity selectively clears ROS-generating components and activates antioxidant pathways. Dysregulation of autophagy or excessive ROS accumulation can disrupt this equilibrium, leading to cell death and disorders such as neurodegenerative diseases, cancer, and aging-related pathologies. They reciprocally serve as “pressure signals” and “clearance targets”, synergistically maintaining cellular homeostasis. This review synthesizes insights from current studies to systematically analyze the complex cross-talk between autophagy and oxidative stress in neurodegeneration and evaluates emerging therapeutic strategies targeting this interplay, including autophagy modulators, antioxidants, phytochemicals, and nanomaterials. These advancements offer novel perspectives for developing neuroprotective therapies through therapeutic modulation of the autophagy-oxidative stress axis. Finally, we summarize key challenges in the field and propose potential directions for future research.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107283"},"PeriodicalIF":5.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030447","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}
Pub Date : 2026-01-18DOI: 10.1016/j.nbd.2026.107277
Lindsay M. Roth, Olga Morozova, Jan Stöhr, Jason Schapansky
Parkinson's Disease (PD) is a neurodegenerative disorder that results from a loss of dopaminergic neurons in the substantia nigra. A pathological hallmark of PD is proteinaceous inclusions called Lewy body aggregates, which consist primarily of misfolded neuronal alpha-synuclein (αSyn). PD pathology progression is thought to be driven by a prion-like spread of αSyn aggregates between adjacent neurons; however, the role of other cell types, such as pathology bearing astrocytes, in this process is still elusive.
αSyn pathology has been observed in PD patient astrocytes, suggesting that astrocytes could be involved in the processing of aggregates. Therefore, we examined the interaction of astrocytes with αSyn pre-formed fibrils (PFFs) and explored how these cells might modulate the spread of seed-competent αSyn in astrocyte–neuron co-cultures. Isolated primary astrocytes rapidly internalized and degraded αSyn PFFs within hours of internalization. Upon exposure to lysosome compromising agents, such as chloroquine or cathepsin B inhibitors leupeptin or CA-074, degradation of αSyn PFFs was significantly reduced. The addition of astrocytes to primary neuron cultures reduced endogenous αSyn aggregation caused by exogenous αSyn PFFs, indicating that astrocytes may mitigate αSyn pathology in the brain. The addition of lysosome-compromised (LC) astrocytes to primary neuron cultures limited this anti-seeding effect. Finally, LC astrocytes, preloaded with PFFs and added to neuronal cultures, induced αSyn pathology in neurons, whereas unimpaired, PFF-preloaded astrocytes did not. These data suggest that astrocytes can modulate and contribute to the spread of αSyn pathology, significantly contributing to PD pathogenesis.
{"title":"Astrocytic lysosome deficits reduce alpha-synuclein degradation and induce the spread of pathology","authors":"Lindsay M. Roth, Olga Morozova, Jan Stöhr, Jason Schapansky","doi":"10.1016/j.nbd.2026.107277","DOIUrl":"10.1016/j.nbd.2026.107277","url":null,"abstract":"<div><div>Parkinson's Disease (PD) is a neurodegenerative disorder that results from a loss of dopaminergic neurons in the substantia nigra. A pathological hallmark of PD is proteinaceous inclusions called Lewy body aggregates, which consist primarily of misfolded neuronal alpha-synuclein (αSyn). PD pathology progression is thought to be driven by a prion-like spread of αSyn aggregates between adjacent neurons; however, the role of other cell types, such as pathology bearing astrocytes, in this process is still elusive.</div><div>αSyn pathology has been observed in PD patient astrocytes, suggesting that astrocytes could be involved in the processing of aggregates. Therefore, we examined the interaction of astrocytes with αSyn pre-formed fibrils (PFFs) and explored how these cells might modulate the spread of seed-competent αSyn in astrocyte–neuron co-cultures. Isolated primary astrocytes rapidly internalized and degraded αSyn PFFs within hours of internalization. Upon exposure to lysosome compromising agents, such as chloroquine or cathepsin B inhibitors leupeptin or CA-074, degradation of αSyn PFFs was significantly reduced. The addition of astrocytes to primary neuron cultures reduced endogenous αSyn aggregation caused by exogenous αSyn PFFs, indicating that astrocytes may mitigate αSyn pathology in the brain. The addition of lysosome-compromised (LC) astrocytes to primary neuron cultures limited this anti-seeding effect. Finally, LC astrocytes, preloaded with PFFs and added to neuronal cultures, induced αSyn pathology in neurons, whereas unimpaired, PFF-preloaded astrocytes did not. These data suggest that astrocytes can modulate and contribute to the spread of αSyn pathology, significantly contributing to PD pathogenesis.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107277"},"PeriodicalIF":5.6,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011398","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}
Essential tremor (ET) is one of the most prevalent neurological diseases and is recognized as a disorder involving multiple neural network dysfunctions. Previous resting-state fMRI studies in ET ignored brain network important dynamic nature. This study aimed to investigate the alterations of dynamic functional connectivity (DFC) and its functional topology in ET.
Methods
Resting-state fMRI data were collected from 144 ET and 131 normal controls (NC). Sliding-window approach with K-means clustering algorithm was used to identify dynamic functional states and graph theory analysis was performed to explore related topological organization of each state in ET.
Results
Two distinct and switchable DFC states (State 1: “cerebrum-dominant” state, with hyperconnected functional architecture in cerebrum; State 2: “cerebellum-dominant” state, with higher functional independence in cerebellum) were identified. Compared to NC, higher fractional windows and longer mean dwell time of cerebellum-dominant state, and fewer state transitions were observed in ET. Higher fractional windows and longer dwell time of cerebellum-dominant state were correlated with more severe tremor. In the topological analysis, compared to NC, ET demonstrated decreased nodal degree centrality and nodal efficiency in cerebrum regions (e.g., orbital inferior frontal gyrus and temporal pole) within two states, but increased nodal betweenness centrality in cerebellum regions (e.g., Cerebellum Crus 2 and Vermis) within cerebellum-dominant state.
Conclusions
These findings revealed that ET was characterized by prolonged cerebellum-dominant state and disrupted functional topology within both states, providing novel insights for better understanding the fundamental neurobiological mechanisms in ET.
{"title":"Disrupted dynamic brain network and its functional topological underpinning in essential tremor","authors":"Weijin Yuan , Xiaojie Duanmu , Qianshi Zheng , Cheng Zhou , Qingze Zeng , Zihao Zhu , Tao Guo , Jiaqi Wen , Chenqing Wu , Haoting Wu , Jianmei Qin , Yuelin Fang , Bingting Zhu , Lifang Wang , Ziyi Zhu , Yaping Yan , Jun Tian , Baorong Zhang , Guohua Zhao , Minming Zhang , Xiaojun Xu","doi":"10.1016/j.nbd.2026.107274","DOIUrl":"10.1016/j.nbd.2026.107274","url":null,"abstract":"<div><h3>Background</h3><div>Essential tremor (ET) is one of the most prevalent neurological diseases and is recognized as a disorder involving multiple neural network dysfunctions. Previous resting-state fMRI studies in ET ignored brain network important dynamic nature. This study aimed to investigate the alterations of dynamic functional connectivity (DFC) and its functional topology in ET.</div></div><div><h3>Methods</h3><div>Resting-state fMRI data were collected from 144 ET and 131 normal controls (NC). Sliding-window approach with K-means clustering algorithm was used to identify dynamic functional states and graph theory analysis was performed to explore related topological organization of each state in ET.</div></div><div><h3>Results</h3><div>Two distinct and switchable DFC states (State 1: “cerebrum-dominant” state, with hyperconnected functional architecture in cerebrum; State 2: “cerebellum-dominant” state, with higher functional independence in cerebellum) were identified. Compared to NC, higher fractional windows and longer mean dwell time of cerebellum-dominant state, and fewer state transitions were observed in ET. Higher fractional windows and longer dwell time of cerebellum-dominant state were correlated with more severe tremor. In the topological analysis, compared to NC, ET demonstrated decreased nodal degree centrality and nodal efficiency in cerebrum regions (e.g., orbital inferior frontal gyrus and temporal pole) within two states, but increased nodal betweenness centrality in cerebellum regions (e.g., Cerebellum Crus 2 and Vermis) within cerebellum-dominant state.</div></div><div><h3>Conclusions</h3><div>These findings revealed that ET was characterized by prolonged cerebellum-dominant state and disrupted functional topology within both states, providing novel insights for better understanding the fundamental neurobiological mechanisms in ET.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107274"},"PeriodicalIF":5.6,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994538","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}
Pub Date : 2026-01-14DOI: 10.1016/j.nbd.2026.107275
Yukun Feng , Wei Zhang , Yinhao Xu , Qi Chang , Hao Zhou , Chunmei Wen , Jingzhe Li , Xiao Hu , Yi Xing , Da Zhang , Peiyu Huang , Junjie Zheng , Weiguo Liu
Background
Increasing evidence suggests that pathological damage in Parkinson's disease (PD) involves the cerebellum, thus resulting in structural and functional alterations. However, whether these alterations predict the progression of cognitive impairment in PD remains unclear.
Methods
We recruited 30 healthy controls and 72 PD patients across different cognitive states with available plasma biomarker data. We used voxel-based morphometry to identify cerebellar atrophy and subsequently performed seed-based whole-brain voxel-wise Granger causality analysis (GCA) on these regions to map cerebello-cerebral effective connectivity. Cerebellar compensatory capacity thresholds were determined through restricted cubic splines and threshold effect analysis. We applied these thresholds to stratify patients in two independent cohorts from the Parkinson's Progression Markers Initiative (n = 106) and an in-house dataset (n = 87); moreover, we conducted Kaplan-Meier survival curve analyses to predict longitudinal cognitive decline risk.
Results
Our study revealed cerebellar atrophy in the left Crus I, right Crus II, and right lobule VI. Cross-sectionally, we identified a dynamic functional connectivity alteration pattern and critical threshold with significant differences in phosphorylated tau 217, glial fibrillary acidic protein, and neurofilament light chain. Subsequently, findings from two longitudinal cohorts further revealed that patients exceeding this threshold exhibited a significantly increased risk of cognitive decline over time.
Conclusions
Our study indicates that the effective connectivity threshold from Crus I to the inferior frontal gyrus may predict short-term cognitive decline. These findings highlight the role of the cerebellum in PD-related cognitive decline and may provide important insights for early intervention strategies.
{"title":"Cerebellar contributions to cognitive deterioration in Parkinson's disease: Insights from multi-omics and longitudinal data","authors":"Yukun Feng , Wei Zhang , Yinhao Xu , Qi Chang , Hao Zhou , Chunmei Wen , Jingzhe Li , Xiao Hu , Yi Xing , Da Zhang , Peiyu Huang , Junjie Zheng , Weiguo Liu","doi":"10.1016/j.nbd.2026.107275","DOIUrl":"10.1016/j.nbd.2026.107275","url":null,"abstract":"<div><h3>Background</h3><div>Increasing evidence suggests that pathological damage in Parkinson's disease (PD) involves the cerebellum, thus resulting in structural and functional alterations. However, whether these alterations predict the progression of cognitive impairment in PD remains unclear.</div></div><div><h3>Methods</h3><div>We recruited 30 healthy controls and 72 PD patients across different cognitive states with available plasma biomarker data. We used voxel-based morphometry to identify cerebellar atrophy and subsequently performed seed-based whole-brain voxel-wise Granger causality analysis (GCA) on these regions to map cerebello-cerebral effective connectivity. Cerebellar compensatory capacity thresholds were determined through restricted cubic splines and threshold effect analysis. We applied these thresholds to stratify patients in two independent cohorts from the Parkinson's Progression Markers Initiative (<em>n</em> = 106) and an in-house dataset (<em>n</em> = 87); moreover, we conducted Kaplan-Meier survival curve analyses to predict longitudinal cognitive decline risk.</div></div><div><h3>Results</h3><div>Our study revealed cerebellar atrophy in the left Crus I, right Crus II, and right lobule VI. Cross-sectionally, we identified a dynamic functional connectivity alteration pattern and critical threshold with significant differences in phosphorylated tau 217, glial fibrillary acidic protein, and neurofilament light chain. Subsequently, findings from two longitudinal cohorts further revealed that patients exceeding this threshold exhibited a significantly increased risk of cognitive decline over time.</div></div><div><h3>Conclusions</h3><div>Our study indicates that the effective connectivity threshold from Crus I to the inferior frontal gyrus may predict short-term cognitive decline. These findings highlight the role of the cerebellum in PD-related cognitive decline and may provide important insights for early intervention strategies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107275"},"PeriodicalIF":5.6,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990094","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}
Pub Date : 2026-01-13DOI: 10.1016/j.nbd.2026.107257
Jinghan Huang , Habbiburr Rehman , Chinh Doan , Thor D. Stein , Jesse Mez , Ting Fang Alvin Ang , Qiushan Tao , Rhoda Au , Lindsay A. Farrer , Xiaoling Zhang , Wei Qiao Qiu
Background
C-reactive protein (CRP) is a key marker of systemic inflammation that affects blood vessel endothelial function, including in the brain. Since endothelial dysfunction is linked to Alzheimer’s disease (AD), we investigated whether elevated CRP level interacts with genetic pathways in brain endothelial cells to influence AD risk.
Methods
Using AD genome-wide association study (GWAS) data, we developed multiple polygenic risk scores (PRSs) including single nucleotide polymorphisms (SNPs) in genes expressed in brain endothelial cells, excluding the APOE region, that are involved in inflammation, synaptic transmission, and other pathways.
Results
Analysis across three independent cohorts revealed that individuals with low inflammatory PRSs (<50%) and elevated blood CRP level were associated with an increased risk of AD; in contrast, those with high inflammatory PRSs (≥50%) did not exhibit this CRP-related AD risk increase. Further examination of individuals with a low inflammatory PRS showed that elevated CRP was associated with lower cerebrospinal fluid (CSF) Aβ42 level and temporal lobe atrophy. Among individuals with a high inflammatory PRS, elevated CRP level was negatively correlated with CSF pTau181 and brain tauopathy, suggesting a potential protective mechanism against tau pathology. Key inflammatory PRS genes, which were impacted by circulating CRP for AD, included APP, IL6ST, and FN1, are involved in amyloid pathology, wound healing, and coagulation.
Conclusion
Our findings highlight two distinct genetic-dose dependent backgrounds: "vulnerable" (<50% inflammatory PRS) and "resilient" (≥50% inflammatory PRS), and support a Genome-Internal Environment (GIE) interaction model, linking peripheral inflammation to AD risk.
c反应蛋白（CRP）是影响血管内皮功能的全身性炎症的关键标志物，包括在大脑中。由于内皮功能障碍与阿尔茨海默病（AD）有关，我们研究了CRP水平升高是否与脑内皮细胞的遗传途径相互作用，从而影响AD的风险。方法利用AD全基因组关联研究（GWAS）数据，我们建立了多个多基因风险评分（PRSs），包括脑内皮细胞中表达的基因的单核苷酸多态性（snp），不包括APOE区域，这些基因参与炎症、突触传递和其他途径。结果：三个独立队列的分析显示，低炎症PRSs（50%）和血液CRP水平升高的个体与AD风险增加相关；相比之下，那些炎症性PRSs高（≥50%）的患者没有表现出与crp相关的AD风险增加。对低炎性PRS患者的进一步检查显示，CRP升高与脑脊液（CSF） a β42水平降低和颞叶萎缩有关。在高炎性PRS患者中，CRP水平升高与脑脊液pTau181和脑病呈负相关，提示可能存在针对tau病理的保护机制。AD的关键炎性PRS基因，包括APP、IL6ST和FN1，受循环CRP影响，参与淀粉样蛋白病理、伤口愈合和凝血。我们的研究结果强调了两种不同的遗传剂量依赖背景：“易感”（<；50%炎症PRS）和“弹性”（≥50%炎症PRS），并支持基因组-内环境（G×IE）相互作用模型，将外周炎症与AD风险联系起来。
{"title":"Circulating C-reactive protein influences polygenic risk of inflammatory genes expressed in brain endothelia for Alzheimer’s disease","authors":"Jinghan Huang , Habbiburr Rehman , Chinh Doan , Thor D. Stein , Jesse Mez , Ting Fang Alvin Ang , Qiushan Tao , Rhoda Au , Lindsay A. Farrer , Xiaoling Zhang , Wei Qiao Qiu","doi":"10.1016/j.nbd.2026.107257","DOIUrl":"10.1016/j.nbd.2026.107257","url":null,"abstract":"<div><h3>Background</h3><div>C-reactive protein (CRP) is a key marker of systemic inflammation that affects blood vessel endothelial function, including in the brain. Since endothelial dysfunction is linked to Alzheimer’s disease (AD), we investigated whether elevated CRP level interacts with genetic pathways in brain endothelial cells to influence AD risk.</div></div><div><h3>Methods</h3><div>Using AD genome-wide association study (GWAS) data, we developed multiple polygenic risk scores (PRSs) including single nucleotide polymorphisms (SNPs) in genes expressed in brain endothelial cells, excluding the <em>APOE</em> region, that are involved in inflammation, synaptic transmission, and other pathways.</div></div><div><h3>Results</h3><div>Analysis across three independent cohorts revealed that individuals with low inflammatory PRSs (<50%) and elevated blood CRP level were associated with an increased risk of AD; in contrast, those with high inflammatory PRSs (≥50%) did not exhibit this CRP-related AD risk increase. Further examination of individuals with a low inflammatory PRS showed that elevated CRP was associated with lower cerebrospinal fluid (CSF) Aβ42 level and temporal lobe atrophy. Among individuals with a high inflammatory PRS, elevated CRP level was negatively correlated with CSF pTau181 and brain tauopathy, suggesting a potential protective mechanism against tau pathology. Key inflammatory PRS genes, which were impacted by circulating CRP for AD, included <em>APP</em>, <em>IL6ST</em>, and <em>FN1</em>, are involved in amyloid pathology, wound healing, and coagulation.</div></div><div><h3>Conclusion</h3><div>Our findings highlight two distinct genetic-dose dependent backgrounds: \"vulnerable\" (<50% inflammatory PRS) and \"resilient\" (≥50% inflammatory PRS), and support a Genome-Internal Environment (G<span><math><mo>×</mo></math></span>IE) interaction model, linking peripheral inflammation to AD risk.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107257"},"PeriodicalIF":5.6,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145979244","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号