Frontiers in Cellular Neuroscience最新文献

{"title":"Loss of epigenetic adaptation to a high-fat diet in alpha-synuclein transgenic mice.","authors":"Vivien Hoof, Samantha L Schaffner, Kristy Dever, Julie MacIsaac, Carola Rotermund, Michael S Kobor, Philipp J Kahle, Thomas Hentrich, Julia M Schulze-Hentrich","doi":"10.3389/fncel.2026.1901103","DOIUrl":"https://doi.org/10.3389/fncel.2026.1901103","url":null,"abstract":"<p><strong>Introduction: </strong>In humans, a high-fat diet and obesity are associated with a higher risk and accelerated progression of Parkinson's disease (PD). Similarly, in animal models a high-fat diet exacerbates PD-related phenotypes, including dopaminergic neurodegeneration, and alpha-synuclein aggregation. We previously demonstrated that transgenic mice overexpressing human, mutated A30P alpha-synuclein failed to transcriptionally adapt to metabolic stress which could be a potential explanation for the high-fat diet-dependent aggravation of PD pathology. However, the underlying epigenetic mechanisms that might regulate this impaired response remained unknown.</p><p><strong>Methods: </strong>Here, we profiled genome-wide DNA methylation and hydroxymethylation in brainstem and hippocampus of wild type and transgenic mice exposed to a long-term standard or high-fat diet.</p><p><strong>Results: </strong>Wild type mice displayed pronounced diet-dependent adaptations that were largely missing in transgenic mice. In the brainstem, a high-fat diet increased the epigenetic age and induced a loss of DNA methylation of neuronal genes involved in protein degradation and mitochondrial metabolism-changes that were largely driven by DNA hydroxymethylation and absent in transgenic mice. Integration of methylation and gene expression data further revealed shared, and brain region-specific interaction networks implicated in metabolism, proteostatis, and neuronal pathways showing molecular adaptation specifically in wild type mice upon high-fat diet.</p><p><strong>Discussion: </strong>Together, these findings point to failure of high-fat diet-induced epigenetic adaptability under alpha-synuclein overexpression, suggesting that altered DNA methylation and DNA hydroxymethylation might contribute to diet-dependent acceleration of PD pathology.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1901103"},"PeriodicalIF":4.4,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13485732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148790258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Growth hormone restrains inflammatory activity of microglia/macrophages in CNS autoimmunity.","authors":"Anica Zivkovic, Milica Lazarević, Ivana Stevanovic, Danijela Laketa, Đorđe Miljković, Irena Lavrnja","doi":"10.3389/fncel.2026.1828468","DOIUrl":"https://doi.org/10.3389/fncel.2026.1828468","url":null,"abstract":"<p><p>Growth hormone (GH) has been implicated in immune regulation, but its effects on microglia/macrophages during neuroinflammation remain insufficiently characterized. Here, we investigated the impact of GH on microglia/macrophages activation using complementary <i>in vitro</i> and <i>in vivo</i> approaches. In LPS-stimulated BV2 microglia, GH induced anti-inflammatory and antioxidant responses, accompanied by morphological features consistent with reduced cellular activation. <i>In vivo</i>, GH administration in rats with experimental autoimmune encephalomyelitis (EAE) delayed disease onset and significantly reduced disease duration, severity, and cumulative clinical score. GH also affected peripheral immune responses, as evidenced by decreased production of the pro-inflammatory cytokines interferon-γ and interleukin-17 by lymph node cells draining the site of the immunization. However, the major effect of GH was observed in the central nervous system, where GH profoundly altered the inflammatory amoeboid morphology of microglia/macrophages typically observed at the EAE peak. Quantitative morphometric, skeleton, and fractal analyses of microglia/macrophages demonstrated reduced process complexity, decreased cell area and perimeter, increased circularity and solidity, reduced fractal dimension and lacunarity, and diminished branching parameters, accompanied by increased iNOS expression at the EAE peak. GH treatment prevented these changes, restoring microglia/macrophages morphological complexity and attenuating pro-inflammatory features. Collectively, these findings indicate that GH modulates neuroinflammatory responses by regulating the microglia/macrophages activation state, supporting a more ramified, surveillant microglia/macrophages phenotype. This positions GH as a disease phase-sensitive regulator of neuroinflammatory processes relevant to autoimmune disorders of the central nervous system.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1828468"},"PeriodicalIF":4.4,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13481192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148790262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurogenesis defects in iPSC-derived midbrain organoids of early-onset Parkinson's disease with 22q11.2 deletion syndrome.","authors":"Syugo Ueki, Toshiya Kimura, Rie Tohge, Atsushi Tamada, Mitsuaki Oki, Yusuke Yakushiji, Haruhisa Inoue, Satoshi Kaneko, Keiko Muguruma","doi":"10.3389/fncel.2026.1906023","DOIUrl":"https://doi.org/10.3389/fncel.2026.1906023","url":null,"abstract":"<p><p>Sporadic Parkinson's disease (PD) is typically a late-onset disorder caused by a combination of genetics, environment, and aging, manifesting when the loss of midbrain dopaminergic neurons exceeds a critical threshold, usually after the age of 50. Conversely, early-onset PD, as observed in cases linked to <i>parkin (PRKN)</i> gene mutations, suggests mechanisms involving either accelerated postnatal neuron loss or an insufficient number of neurons at birth. Patients with the 22q11.2 deletion syndrome (DS) have a significantly higher prevalence of early-onset PD. The absence of known genes associated with hereditary PD in the deleted region suggests the involvement of novel, non-traditional risk factors. This could potentially implicate the neurodevelopmental origin of dopaminergic neurons arising from the floor plate. To investigate this hypothesis, we generated midbrain organoids from induced pluripotent stem cells derived from a patient with 22q11.2 DS. The organoids recapitulated key aspects of <i>in vivo</i> neurogenesis, revealing enhanced differentiation of dopaminergic neurons in 22q11.2DS- and <i>PRKN</i>-derived organoids compared to controls on days 28 and 56 of culture. These findings suggest that, in early-onset PD patients with 22q11.2 DS or <i>PRKN</i> mutation, enhanced neurogenesis could result in reduced number of dopaminergic neurons during early development. The organoids of early-onset PD demonstrated that progenitors undergo enhanced differentiation at an early stage. This suggests that the atypical developmental process could reduce progenitors before there are enough mature dopaminergic neurons. This in turn indicates that the onset of PD may occur as early as the embryonic stage.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1906023"},"PeriodicalIF":4.4,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13472798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148764471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Glutamate imaging reveals multiple sites of stochastic release in the CA3 giant mossy fiber boutons.","authors":"Sylvain Rama, Thomas P Jensen, Dmitri A Rusakov","doi":"10.3389/fncel.2026.1932278","DOIUrl":"https://doi.org/10.3389/fncel.2026.1932278","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fncel.2019.00243.].</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1932278"},"PeriodicalIF":4.4,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13473803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148764089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective retinal neuron loss and impaired neurovascular support underlie myopic retinopathy in RPE-specific Lrp2-deficient mice.","authors":"Jinyan Qi, Xuexue Cui, Caijiao Yi, Jian Liu, Wen Deng, Xiang-Ling Yuan, Yuanyuan Hu, Tong Wang, Heping Xu","doi":"10.3389/fncel.2026.1856140","DOIUrl":"https://doi.org/10.3389/fncel.2026.1856140","url":null,"abstract":"<p><p>Pathologic myopia is a major cause of irreversible visual impairment worldwide and is characterized by excessive axial elongation accompanied by progressive retinal degeneration. Whether vision loss results primarily from passive retinal stretching or selective neurodegeneration remains unclear, hindering the development of effective neuroprotective and regenerative therapies. Here, we investigated retinal neuronal, vascular, and glial alterations in retinal pigment epithelium (RPE)-specific Lrp2 knockout (Best1-Cre/Lrp2^fl/fl conditional knockout, CKO) model of pathologic myopia. The CKO mice were examined longitudinally using multimodal ocular imaging, electroretinography, optokinetic testing, fluorescein angiography, and quantitative immunohistochemistry analysis. CKO phenotype⁺ mice developed early-onset, progressive axial elongation and high myopia, accompanied by fundus features closely resembling human pathologic myopia, including peripapillary and patchy chorioretinal atrophy. Retinal function was markedly impaired, with significant reductions in scotopic a-, b-, and c-wave amplitudes. Although axial elongation resulted in a 1.98-fold increase in retinal surface area and a 55.95% reduction in retinal thickness, quantitative correction for retinal expansion revealed selective neuronal loss rather than uniform retinal degeneration. Total numbers of rods, cones, horizontal cells, and GABAergic amacrine cells were reduced by 22, 40, 30, and 57%, respectively, together with a 66% loss of photoreceptor synaptic ribbons. In contrast, retinal ganglion cells and bipolar cells exhibited reduced density but preserved absolute cell numbers. These neuronal changes were accompanied by retinal and choroidal microvascular degeneration, Müller gliosis, microglial activation and subretinal accumulation, and RPE dysmorphology. Our findings demonstrate that axial elongation induces neuron subtype-specific degeneration rather than generalized retinal thinning. Our study identifies photoreceptors, horizontal cells, and inhibitory amacrine cells as particularly vulnerable populations and implicates impaired RPE support, neurovascular dysfunction, and chronic glial activation as key mechanisms driving myopic retinopathy. This study provides a mechanistic framework for developing targeted neuroprotective and regeneration-based therapies for pathologic myopia.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1856140"},"PeriodicalIF":4.4,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13467757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated meta-analysis of human astrocytes transcriptomes reveals a candidate recurrent inflammatory signature in response to inflammatory and immune stimuli.","authors":"Andrea Luque-Bolivar, Karem Ruiz-Araujo, Andrés Felipe Aristizábal-Pachón, Janneth González","doi":"10.3389/fncel.2026.1870142","DOIUrl":"10.3389/fncel.2026.1870142","url":null,"abstract":"<p><p>Astrocytes are key regulators of inflammatory and immune responses in the central nervous system, particularly under pathological conditions. We conducted a systematic search of the NCBI GEO and ENA databases to identify transcriptomic studies of stimulated astrocytes. This meta-analysis integrates 11 RNA-Seq datasets, encompassing a total of 153 samples (91 stimulated, and 62 controls) exposed to pro-inflammatory stimuli such as cytokines (TNF-α, IL-6, and IL-1β), palmitic acid, and pathogens like SARS-CoV-2 and <i>Borrelia burgdorferi</i>. Through robust rank aggregation (RRA), we identified 130 differentially expressed genes (DEGs), including 125 upregulated and 5 downregulated. Functional enrichment analyses revealed that these DEGs are primarily involved in immune and inflammatory pathways, such as cytokine signaling, interferon responses, and NF-κB activation. Network analysis revealed five hub nodes, CXCL10, DDX58, IFIH1, IL-1β, and TLR3, underscoring their importance in astrocytic inflammatory signaling. These findings emphasize the ability of astrocytes to act as immunocompetent cells that coordinate inflammatory responses through mechanisms such as the NOD-like receptor and NF-κB pathways. Although chronic activation of NF-κB has been linked to inflammation, this pathway also plays essential roles in synaptic plasticity. Moreover, the consistent upregulation of <i>DDX58</i> and <i>IFIH1</i> across varied inflammatory stimuli suggests that astrocytes transition into a common 'reactive' state that may contribute to chronic neuroinflammation. This study identifies a candidate gene signature and underscores the dual protective and pathological roles of astrocytes in inflammatory processes.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1870142"},"PeriodicalIF":4.4,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148725587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LRRK2 G2019S reprograms innate and adaptive immunity to drive context-dependent host defense outcomes.","authors":"Andrea R Merchak, Mary K Herrick, Madelyn C Houser, Dina A Moustafa, Joanna B Goldberg, Jeremy M Boss, Jacob Kohlmeier, Darcie M Cook, Cody E Keating, Jianjun Chang, Andrew B West, Malú Gámez Tansey","doi":"10.3389/fncel.2026.1860967","DOIUrl":"10.3389/fncel.2026.1860967","url":null,"abstract":"<p><strong>Introduction: </strong>Parkinson's disease (PD) is increasingly recognized as a neurological disorder characterized not only by neurodegeneration but also by chronic immune dysregulation across the lifespan. Although the initiating events underlying PD remain unclear, accumulating evidence suggests that inflammatory processes may contribute to disease susceptibility and progression. Mutations in leucine-rich repeat kinase 2 (<i>LRRK2</i>), particularly the gain-of-function G2019S variant, represent the common genetic cause of familial PD and have been implicated in immune regulation and infection susceptibility. To date, most research has focused on the effect of <i>LRRK2</i> mutation in neurons and the contributions of G2019S-mediated kinase activity to neuronal toxicity, leaving the role of G2019S-mediated kinase activity in immune cell homeostasis and its contribution to PD pathogenesis largely unresolved.</p><p><strong>Methods: </strong>Here, we used murine overexpression models of wildtype and G2019S variant of mouse <i>Lrrk2</i> to examine how <i>Lrrk2</i> G2019S shapes host defense across viral and bacterial infection models. We tested systemic sepsis and <i>Escherichia coli</i> infection to examine bacterial clearance. We followed up by testing macrophage responses to intracellular (Listeria monocytogenes) or primarily extracellular (Pseudomonas aeruginosa) bacteria. Finally, tested antibody-mediated immunity using influenza and cytotoxic T cell-mediated immunity using lymphocytic choriomeningitis virus (LCMV) infection.</p><p><strong>Results: </strong>We found that <i>Lrrk2</i> G2019S overexpression enhanced survival and bacterial clearance during P. aeruginosa lung infection, whereas the same genotype worsened outcomes in polymicrobial sepsis, with increased mortality, pulmonary myeloid infiltration and a hematopoietic cell-intrinsic phenotype. During L. monocytogenes infection, <i>Lrrk2</i> G2019S selectively reduced non-classical monocytes without altering disease progression. In influenza and LCMV infection, G2019S altered antigen-specific CD8⁺ T cell distribution without major changes in cell memory responses clinical severity.</p><p><strong>Discussion: </strong>Together, these data show that <i>Lrrk2</i> G2019S selectively reprograms innate and adaptive immunity in a pathogen- and tissue-dependent manner, uncoupling inflammatory magnitude from effective host defense. These results and previous work support a model in which the G2019S <i>LRRK2</i> variant contributes to maladaptive inflammatory responses to specific infection challenges, providing insight into how lifetime immune perturbations may intersect with genetic susceptibility to influence lifetime infection risk.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1860967"},"PeriodicalIF":4.4,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148724916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Neuro-immune interaction in disease.","authors":"Na Sun, Marta Celorrio, Yiying Zhang, Xiaoying Chen","doi":"10.3389/fncel.2026.1931155","DOIUrl":"10.3389/fncel.2026.1931155","url":null,"abstract":"","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1931155"},"PeriodicalIF":4.4,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13461450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148721064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD22 regulates Aβ clearance in microglia through INPP5D signaling.","authors":"De-Zhi Zou, Jun Li, Qiu-Shuang Long, Ruo-Qi Zhang, Bing-Lin Zhu, Jia-Ze Tan","doi":"10.3389/fncel.2026.1886995","DOIUrl":"10.3389/fncel.2026.1886995","url":null,"abstract":"<p><strong>Introduction: </strong>Impaired microglial clearance of amyloid-β (Aβ) is a central driver of Alzheimer's disease (AD), yet the mechanisms governing intracellular Aβ degradation remain poorly defined.</p><p><strong>Methods: </strong>We investigated the role of CD22 in microglial Aβ processing using primary microglia, transcriptomic profiling, and hippocampal samples from AD patients and transgenic mice.</p><p><strong>Results: </strong>We identified CD22 as an Aβ-inducible signaling regulator that restrains microglial Aβ processing. CD22 expression was elevated in the hippocampus of AD patients and transgenic mice and was rapidly induced by Aβ in microglia. Functionally, <i>CD22</i> knockdown enhanced intracellular Aβ degradation without affecting initial uptake. Transcriptomic profiling identified the AD risk gene INPP5D as a key downstream effector of CD22. Loss of <i>CD22</i> suppressed INPP5D expression and promoted AKT activation, while INPP5D overexpression partially rescued the enhanced Aβ clearance phenotype. These findings define a CD22-INPP5D signaling axis that acts as a molecular brake on microglial Aβ processing. Aβ itself induces CD22 expression, revealing a feed-forward inhibitory loop in which amyloid accumulation limits its own clearance.</p><p><strong>Discussion: </strong>Collectively, these findings identify a regulatory mechanism controlling intracellular Aβ degradation and suggest the CD22-INPP5D axis as a potential therapeutic target for AD.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1886995"},"PeriodicalIF":4.4,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13457040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148711692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From cellular diversity to coordinating nervous system function: the next frontier in non-neuronal cell biology.","authors":"Jason R Plemel","doi":"10.3389/fncel.2026.1934284","DOIUrl":"10.3389/fncel.2026.1934284","url":null,"abstract":"","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"20 ","pages":"1934284"},"PeriodicalIF":4.4,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13457066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148711766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}