Pub Date : 2026-01-05DOI: 10.1186/s13024-025-00921-1
Michael R Duggan,Hamilton Se-Hwee Oh,Philipp Frank,Gabriela T Gomez,David Zweibaum,Yuhan Cui,Jingsha Chen,Aditya Surapaneni,Cassandra O Blew,Heather E Dark,Cassandra M Joynes,Sridhar Kandala,Murat Bilgel,Amelia Farinas,Guray Erus,Qu Tian,Julián Candia,Krishna A Pucha,Bennett A Landman,Logan Dumitrescu,Timothy J Hohman,Alexandria Lewis,Abhay Moghekar,Fatemeh Siavoshi,Muhammad Ali,Menghan Liu,Ying Xu,Daniel Western,Naoto Kaneko,Shintaro Kato,Makio Furuichi,Masaki Shibayama,Masahisa Katsuno,Yukiko Nishita,Rei Otsuka,Rebecca F Gottesman,Eric B Dammer,Nicholas T Seyfried,Allan I Levey,Erik C B Johnson,Elizabeth Mormino,Anthony D Wagner,Kathleen L Poston,Dimitrios Kapogiannis,Morgan E Grams,Pavan Bhargava,Iwao Waga,Christos Davatzikos,Susan M Resnick,Luigi Ferrucci,David A Bennett,Carlos Cruchaga,Tony Wyss-Coray,Mika Kivimäki,Josef Coresh,Keenan A Walker
BACKGROUNDBiofluid proteomics can enhance our understanding of the neurodegenerative mechanisms underlying Alzheimer's disease and related dementias (ADRDs). Oligodendrocyte myelin glycoprotein (OMG) is a brain-specific protein implicated in myelination, but its potential mechanistic, biomarker, and therapeutic roles in ADRDs requires further elucidation.METHODSAfter detecting an inverse association between its abundance in peripheral circulation and cortical amyloid deposition in two community-based cohorts, the current study characterized OMG's role in ADRDs with high-throughput proteomics from sixteen independent cohorts. Data included a variety of cross-sectional and longitudinal community-based and clinical cohorts from North America, Europe, and Asia, and incorporated complementary biofluids, biospecimens, and proteomic platforms. Statistical analyses were conducted separately in each cohort.RESULTSWe detected lower plasma OMG in individuals with cortical amyloid deposition, compromised brain structure, dementia, and multiple sclerosis, as well as in individuals who developed dementia over 7- to 20-year follow-up periods. OMG's CSF and brain proteomic signatures reflected broader neuroprotective mechanisms, especially axonal structural integrity, and two-sample Mendelian randomization causally implicated OMG as protective against multiple neurodegenerative diseases.CONCLUSIONSOur findings implicate OMG as a mechanistic determinant of neurodegenerative resiliency among older adults, which is reliably captured by its abundance in peripheral circulation.
{"title":"OMG! A proteomic determinant of neurodegenerative resiliency.","authors":"Michael R Duggan,Hamilton Se-Hwee Oh,Philipp Frank,Gabriela T Gomez,David Zweibaum,Yuhan Cui,Jingsha Chen,Aditya Surapaneni,Cassandra O Blew,Heather E Dark,Cassandra M Joynes,Sridhar Kandala,Murat Bilgel,Amelia Farinas,Guray Erus,Qu Tian,Julián Candia,Krishna A Pucha,Bennett A Landman,Logan Dumitrescu,Timothy J Hohman,Alexandria Lewis,Abhay Moghekar,Fatemeh Siavoshi,Muhammad Ali,Menghan Liu,Ying Xu,Daniel Western,Naoto Kaneko,Shintaro Kato,Makio Furuichi,Masaki Shibayama,Masahisa Katsuno,Yukiko Nishita,Rei Otsuka,Rebecca F Gottesman,Eric B Dammer,Nicholas T Seyfried,Allan I Levey,Erik C B Johnson,Elizabeth Mormino,Anthony D Wagner,Kathleen L Poston,Dimitrios Kapogiannis,Morgan E Grams,Pavan Bhargava,Iwao Waga,Christos Davatzikos,Susan M Resnick,Luigi Ferrucci,David A Bennett,Carlos Cruchaga,Tony Wyss-Coray,Mika Kivimäki,Josef Coresh,Keenan A Walker","doi":"10.1186/s13024-025-00921-1","DOIUrl":"https://doi.org/10.1186/s13024-025-00921-1","url":null,"abstract":"BACKGROUNDBiofluid proteomics can enhance our understanding of the neurodegenerative mechanisms underlying Alzheimer's disease and related dementias (ADRDs). Oligodendrocyte myelin glycoprotein (OMG) is a brain-specific protein implicated in myelination, but its potential mechanistic, biomarker, and therapeutic roles in ADRDs requires further elucidation.METHODSAfter detecting an inverse association between its abundance in peripheral circulation and cortical amyloid deposition in two community-based cohorts, the current study characterized OMG's role in ADRDs with high-throughput proteomics from sixteen independent cohorts. Data included a variety of cross-sectional and longitudinal community-based and clinical cohorts from North America, Europe, and Asia, and incorporated complementary biofluids, biospecimens, and proteomic platforms. Statistical analyses were conducted separately in each cohort.RESULTSWe detected lower plasma OMG in individuals with cortical amyloid deposition, compromised brain structure, dementia, and multiple sclerosis, as well as in individuals who developed dementia over 7- to 20-year follow-up periods. OMG's CSF and brain proteomic signatures reflected broader neuroprotective mechanisms, especially axonal structural integrity, and two-sample Mendelian randomization causally implicated OMG as protective against multiple neurodegenerative diseases.CONCLUSIONSOur findings implicate OMG as a mechanistic determinant of neurodegenerative resiliency among older adults, which is reliably captured by its abundance in peripheral circulation.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"21 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-03DOI: 10.1186/s13024-025-00920-2
Jie Dong, Breanna T Sullivan, Victor M Martinez Smith, Lupeng Wang, Lulu Tian, Justin Kung, Bin Song, Shirong Lin, Andreanna Le, Lixin Sun, Lisa Chang, Jinhui Ding, Weidong Le, Jun Jia, Huaibin Cai
{"title":"Developmental dopamine loss rewires striatal circuits to promote locomotion.","authors":"Jie Dong, Breanna T Sullivan, Victor M Martinez Smith, Lupeng Wang, Lulu Tian, Justin Kung, Bin Song, Shirong Lin, Andreanna Le, Lixin Sun, Lisa Chang, Jinhui Ding, Weidong Le, Jun Jia, Huaibin Cai","doi":"10.1186/s13024-025-00920-2","DOIUrl":"10.1186/s13024-025-00920-2","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":"7"},"PeriodicalIF":17.5,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12866494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22DOI: 10.1186/s13024-025-00918-w
Di Hu,Xiaoyan Sun,Xin Qi
BACKGROUNDMitochondrial dysfunction and α-Synuclein (αSyn) aggregation are defining features of Parkinson's disease (PD), yet the mechanistic link between them remains poorly understood. Although our previous findings suggest that the interaction between αSyn and ClpP (a mitochondrial matrix protease) contributes to PD progression, the pathogenic and therapeutic relevance of this interaction remains elusive.METHODSWe employed biochemical and cell biological approaches to investigate how αSyn and ClpP are mutually regulated. Additionally, we determined the pathogenic impact of αSyn-ClpP interaction by using decoy peptide CS2 in αSyn-PFF inoculated primary neurons, PD patient iPSC-derived dopaminergic neurons, and a transgenic mouse model of PD carrying αSyn-A53T mutation.RESULTSWe identified mitochondrial protease ClpP as a key regulator of αSyn pathology. We show that αSyn interacts with ClpP through its non-amyloid-β component (NAC) domain, leading to impaired ClpP activity and mitochondrial proteotoxic stress. ClpP, in turn, negatively regulates αSyn aggregation and propagation by stabilizing its native tetrameric form. To interrupt this pathogenic interaction, we developed a decoy peptide, CS2, which binds the NAC domain of αSyn and restores ClpP function. CS2 treatment reduced mitochondrial oxidative stress and αSyn neurotoxicity in neuronal cultures, primary cortical neurons inoculated with αSyn preformed fibrils, and dopaminergic neurons derived from PD patient iPSCs. In mThy1-hSNCA transgenic mice, subcutaneous administration of CS2 restored ClpP levels, decreased αSyn pathology and neuroinflammation, and improved both cognitive and motor function.CONCLUSIONThese findings highlight the αSyn-ClpP interaction as a druggable target and support CS2 as a potential disease-modifying therapy for PD and related synucleinopathies.
{"title":"Disrupting α-Synuclein-ClpP interaction restores mitochondrial function and attenuates neuropathology in Parkinson's disease models.","authors":"Di Hu,Xiaoyan Sun,Xin Qi","doi":"10.1186/s13024-025-00918-w","DOIUrl":"https://doi.org/10.1186/s13024-025-00918-w","url":null,"abstract":"BACKGROUNDMitochondrial dysfunction and α-Synuclein (αSyn) aggregation are defining features of Parkinson's disease (PD), yet the mechanistic link between them remains poorly understood. Although our previous findings suggest that the interaction between αSyn and ClpP (a mitochondrial matrix protease) contributes to PD progression, the pathogenic and therapeutic relevance of this interaction remains elusive.METHODSWe employed biochemical and cell biological approaches to investigate how αSyn and ClpP are mutually regulated. Additionally, we determined the pathogenic impact of αSyn-ClpP interaction by using decoy peptide CS2 in αSyn-PFF inoculated primary neurons, PD patient iPSC-derived dopaminergic neurons, and a transgenic mouse model of PD carrying αSyn-A53T mutation.RESULTSWe identified mitochondrial protease ClpP as a key regulator of αSyn pathology. We show that αSyn interacts with ClpP through its non-amyloid-β component (NAC) domain, leading to impaired ClpP activity and mitochondrial proteotoxic stress. ClpP, in turn, negatively regulates αSyn aggregation and propagation by stabilizing its native tetrameric form. To interrupt this pathogenic interaction, we developed a decoy peptide, CS2, which binds the NAC domain of αSyn and restores ClpP function. CS2 treatment reduced mitochondrial oxidative stress and αSyn neurotoxicity in neuronal cultures, primary cortical neurons inoculated with αSyn preformed fibrils, and dopaminergic neurons derived from PD patient iPSCs. In mThy1-hSNCA transgenic mice, subcutaneous administration of CS2 restored ClpP levels, decreased αSyn pathology and neuroinflammation, and improved both cognitive and motor function.CONCLUSIONThese findings highlight the αSyn-ClpP interaction as a druggable target and support CS2 as a potential disease-modifying therapy for PD and related synucleinopathies.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"20 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-15DOI: 10.1186/s13024-025-00916-y
Maria-Tzousi Papavergi,Praveen Bathini,Brijendra Singh,Cynthia A Lemere
{"title":"The complement cascade in Alzheimer's disease: modern implications of an ancient immune protagonist.","authors":"Maria-Tzousi Papavergi,Praveen Bathini,Brijendra Singh,Cynthia A Lemere","doi":"10.1186/s13024-025-00916-y","DOIUrl":"https://doi.org/10.1186/s13024-025-00916-y","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"21 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1186/s13024-025-00915-z
Kazi Md Mahmudul Hasan, Lisa M Barnhill, Kimberly C Paul, Chao Peng, William Zeiger, Beate Ritz, Marisol Arellano, Michael Ajnassian, Shujing Zhang, Aye Theint Theint, Gazmend Elezi, Hilli Weinberger, Julian P Whitelegge, Qing Bai, Sharon Li, Edward A Burton, Jeff M Bronstein
{"title":"The pesticide chlorpyrifos increases the risk of Parkinson's disease.","authors":"Kazi Md Mahmudul Hasan, Lisa M Barnhill, Kimberly C Paul, Chao Peng, William Zeiger, Beate Ritz, Marisol Arellano, Michael Ajnassian, Shujing Zhang, Aye Theint Theint, Gazmend Elezi, Hilli Weinberger, Julian P Whitelegge, Qing Bai, Sharon Li, Edward A Burton, Jeff M Bronstein","doi":"10.1186/s13024-025-00915-z","DOIUrl":"10.1186/s13024-025-00915-z","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":"3"},"PeriodicalIF":17.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12801438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1186/s13024-025-00914-0
V Donadio,M Ingelsson,G Rizzo,A Furia,A Incensi,C Delprete,M Pinho,R Liguori,S Pritzkow
{"title":"Diagnostic biomarkers for α-synucleinopathies- state of the art and future developments: a systematic review.","authors":"V Donadio,M Ingelsson,G Rizzo,A Furia,A Incensi,C Delprete,M Pinho,R Liguori,S Pritzkow","doi":"10.1186/s13024-025-00914-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00914-0","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"204 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145674411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDPathogenic tau accumulation drives neurodegeneration in Alzheimer's disease (AD). Enhancing the aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12), highly and selectively expressed by microglia, plays a crucial role in microglial immune responses. Previous studies have shown that tauopathy mice lacking DAP12 exhibit higher tau pathology but are protected from tau pathology-induced cognitive deficits. However, the exact mechanism behind this resilience remains elusive.METHODSWe investigated the effects of DAP12 deletion on tau pathology, as well as tau-induced brain inflammation and neurodegeneration, in homozygous human Tau P301S transgenic mice. In addition, we conducted single-nucleus RNA sequencing of hippocampal tissues to examine cell type-specific transcriptomic changes at the single-cell level. Furthermore, we utilized the CellChat package to profile cell-cell communication in the mouse brain and investigated how these interactions are affected by tau pathology and Dap12 deletion.RESULTSWe demonstrated that Dap12 deletion reduced tau processing in primary microglia and increased tau pathology in female tauopathy mice, with minimal effects on males. Despite this, Dap12 deletion markedly reduced brain inflammation, synapse loss, and demyelination, indicating enhanced resilience to tau toxicity. Single-cell transcriptomic profiling revealed that Dap12 deletion blocked tau-induced alterations in microglia, neurons, and oligodendrocytes. CellChat analysis identified aberrant tau-induced SLIT2 signaling from excitatory neurons to oligodendrocytes. Dap12 deletion suppressed Slit2 upregulation and mitigated demyelination, while lentiviral-Slit2 overexpression induced myelin loss in tauopathy mice. Elevated SLIT2 levels were associated with demyelination in tauopathy mouse model and human AD brains. Spatial transcriptomics revealed a spatial correlation of SLIT2 expression and tau pathology in AD brain tissue.CONCLUSIONSOur study identifies a novel DAP12-dependent mechanistic link between upregulated Slit2 expression in excitatory neurons and oligodendrocyte-dependent myelination loss in tauopathy. Despite elevating tau load, the absence of microglial Dap12 ameliorates neuroinflammation and improves brain functions in tauopathy mice. Our study suggests that selectively targeting the toxic aspects of DAP12 signaling while preserving its beneficial functions may be a promising strategy to enhance brain resilience in AD.
背景：致病性tau积聚驱动阿尔茨海默病（AD）的神经变性。增强老化的大脑对tau病理的恢复能力将导致新的治疗策略。DAP12 （DNAX-activation protein 12）在小胶质细胞中高度选择性表达，在小胶质细胞免疫应答中起着至关重要的作用。先前的研究表明，缺乏DAP12的tau病小鼠表现出更高的tau病理，但可以保护tau病理诱导的认知缺陷。然而，这种弹性背后的确切机制仍然难以捉摸。方法研究DAP12缺失对纯合子人tau P301S转基因小鼠tau病理、tau诱导的脑炎症和神经变性的影响。此外，我们对海马组织进行了单核RNA测序，以在单细胞水平上检测细胞类型特异性转录组变化。此外，我们利用CellChat包来分析小鼠大脑中的细胞-细胞通信，并研究了这些相互作用如何受到tau病理和Dap12缺失的影响。结果我们证明Dap12缺失减少了雌性tau病小鼠原发性小胶质细胞中的tau加工，增加了tau病理，而对雄性的影响很小。尽管如此，Dap12缺失显著减少了脑炎症、突触丢失和脱髓鞘，表明对tau毒性的恢复能力增强。单细胞转录组分析显示，Dap12缺失阻断了tau诱导的小胶质细胞、神经元和少突胶质细胞的改变。CellChat分析发现了异常的tau诱导的SLIT2信号从兴奋性神经元到少突胶质细胞。Dap12缺失抑制了Slit2上调并减轻了脱髓鞘，而慢病毒-Slit2过表达诱导了tau病小鼠的髓磷脂丢失。在牛头病小鼠模型和人类AD大脑中，升高的SLIT2水平与脱髓鞘有关。空间转录组学揭示了AD脑组织中SLIT2表达与tau病理的空间相关性。我们的研究发现了一种新的依赖dap12的机制，在兴奋性神经元中上调的Slit2表达与tau病中依赖少突胶质细胞的髓鞘形成丧失之间存在联系。尽管tau负荷升高，但小胶质细胞Dap12的缺失改善了tau病小鼠的神经炎症并改善了脑功能。我们的研究表明，在保留其有益功能的同时，选择性地靶向DAP12信号的毒性方面可能是增强AD患者大脑恢复能力的一种有希望的策略。
{"title":"DAP12 deletion reduces neuronal SLIT2 and demyelination and enhances brain resilience in female tauopathy mice.","authors":"Hao Chen,Li Fan,Qi Guo,Man Ying Wong,Jingjie Zhu,Nessa Foxe,Winston Wang,Aviram Nessim,Gillian Carling,Bangyan Liu,Chloe Lopez-Lee,Yige Huang,Sadaf Amin,Tark Patel,Sue-Ann Mok,Won-Min Song,Bin Zhang,Shiaoching Gong,Qin Ma,Hongjun Fu,Li Gan,Wenjie Luo","doi":"10.1186/s13024-025-00903-3","DOIUrl":"https://doi.org/10.1186/s13024-025-00903-3","url":null,"abstract":"BACKGROUNDPathogenic tau accumulation drives neurodegeneration in Alzheimer's disease (AD). Enhancing the aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12), highly and selectively expressed by microglia, plays a crucial role in microglial immune responses. Previous studies have shown that tauopathy mice lacking DAP12 exhibit higher tau pathology but are protected from tau pathology-induced cognitive deficits. However, the exact mechanism behind this resilience remains elusive.METHODSWe investigated the effects of DAP12 deletion on tau pathology, as well as tau-induced brain inflammation and neurodegeneration, in homozygous human Tau P301S transgenic mice. In addition, we conducted single-nucleus RNA sequencing of hippocampal tissues to examine cell type-specific transcriptomic changes at the single-cell level. Furthermore, we utilized the CellChat package to profile cell-cell communication in the mouse brain and investigated how these interactions are affected by tau pathology and Dap12 deletion.RESULTSWe demonstrated that Dap12 deletion reduced tau processing in primary microglia and increased tau pathology in female tauopathy mice, with minimal effects on males. Despite this, Dap12 deletion markedly reduced brain inflammation, synapse loss, and demyelination, indicating enhanced resilience to tau toxicity. Single-cell transcriptomic profiling revealed that Dap12 deletion blocked tau-induced alterations in microglia, neurons, and oligodendrocytes. CellChat analysis identified aberrant tau-induced SLIT2 signaling from excitatory neurons to oligodendrocytes. Dap12 deletion suppressed Slit2 upregulation and mitigated demyelination, while lentiviral-Slit2 overexpression induced myelin loss in tauopathy mice. Elevated SLIT2 levels were associated with demyelination in tauopathy mouse model and human AD brains. Spatial transcriptomics revealed a spatial correlation of SLIT2 expression and tau pathology in AD brain tissue.CONCLUSIONSOur study identifies a novel DAP12-dependent mechanistic link between upregulated Slit2 expression in excitatory neurons and oligodendrocyte-dependent myelination loss in tauopathy. Despite elevating tau load, the absence of microglial Dap12 ameliorates neuroinflammation and improves brain functions in tauopathy mice. Our study suggests that selectively targeting the toxic aspects of DAP12 signaling while preserving its beneficial functions may be a promising strategy to enhance brain resilience in AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"198200 1","pages":"124"},"PeriodicalIF":15.1,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1186/s13024-025-00913-1
Antonia Seitz, Taylan Özöncü, Daniela Sinske, Claudia Klugmann, Daniel Tews, Pamela Fischer-Posovszky, Bernd Knöll, Sofia Meyer Zu Reckendorf
Peripheral nerves have an intrinsic capacity for regeneration after traumatic injury, with Schwann cells (SCs) playing a central role in orchestrating this complex process. Critical components of successful regeneration include SC reprogramming into repair SCs, debris removal and metabolic adaptations. Up to now, there are no pharmacological treatments available in the clinics to improve nerve regeneration. In this study, we investigated peroxisome proliferator-activated receptor gamma (PPARɣ) as a therapeutic target in the context of nerve regeneration, since we previously found this transcription factor to be involved in SC reprograming and metabolic adaptations. Therefore, we used a mouse model of sciatic nerve crush injury and applied the PPARɣ agonist pioglitazone (PIO) in two different treatment paradigms: (i) acutely after injury (0-5 days post injury) and (ii) delayed (5-21 days post injury), thereby addressing different phases of regeneration. Our findings revealed that PIO treatment immediately following nerve injury (first treatment paradigm) disrupted SC transition into the repair phenotype and diminished the physiological inflammatory response. As a consequence, axonal and myelin debris clearance was delayed, ultimately resulting in impaired axonal outgrowth and nerve regeneration. In the second treatment paradigm (PIO administration starting five days after injury) SCs had already acquired the repair phenotype and immune cell infiltration had taken place when PIO administration started. There, PIO promoted axonal regeneration, enhanced remyelination, and improved functional recovery. Importantly, PIO treatment increased mitochondrial content in neurons and SCs. In addition, delayed application of PIO induced lipid metabolism, glycolysis and ATP production in SCs, leading to the assumption that improved metabolic conditions mediate enhanced nerve regeneration in this treatment paradigm. These findings show that depending on the timing of PIO treatment, PPARɣ can serve as a potential therapeutic agent to improve nerve regeneration by promoting key metabolic adaptations.
{"title":"Pioglitazone modulates metabolic adaptation and peripheral nerve regeneration after injury.","authors":"Antonia Seitz, Taylan Özöncü, Daniela Sinske, Claudia Klugmann, Daniel Tews, Pamela Fischer-Posovszky, Bernd Knöll, Sofia Meyer Zu Reckendorf","doi":"10.1186/s13024-025-00913-1","DOIUrl":"10.1186/s13024-025-00913-1","url":null,"abstract":"<p><p>Peripheral nerves have an intrinsic capacity for regeneration after traumatic injury, with Schwann cells (SCs) playing a central role in orchestrating this complex process. Critical components of successful regeneration include SC reprogramming into repair SCs, debris removal and metabolic adaptations. Up to now, there are no pharmacological treatments available in the clinics to improve nerve regeneration. In this study, we investigated peroxisome proliferator-activated receptor gamma (PPARɣ) as a therapeutic target in the context of nerve regeneration, since we previously found this transcription factor to be involved in SC reprograming and metabolic adaptations. Therefore, we used a mouse model of sciatic nerve crush injury and applied the PPARɣ agonist pioglitazone (PIO) in two different treatment paradigms: (i) acutely after injury (0-5 days post injury) and (ii) delayed (5-21 days post injury), thereby addressing different phases of regeneration. Our findings revealed that PIO treatment immediately following nerve injury (first treatment paradigm) disrupted SC transition into the repair phenotype and diminished the physiological inflammatory response. As a consequence, axonal and myelin debris clearance was delayed, ultimately resulting in impaired axonal outgrowth and nerve regeneration. In the second treatment paradigm (PIO administration starting five days after injury) SCs had already acquired the repair phenotype and immune cell infiltration had taken place when PIO administration started. There, PIO promoted axonal regeneration, enhanced remyelination, and improved functional recovery. Importantly, PIO treatment increased mitochondrial content in neurons and SCs. In addition, delayed application of PIO induced lipid metabolism, glycolysis and ATP production in SCs, leading to the assumption that improved metabolic conditions mediate enhanced nerve regeneration in this treatment paradigm. These findings show that depending on the timing of PIO treatment, PPARɣ can serve as a potential therapeutic agent to improve nerve regeneration by promoting key metabolic adaptations.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"20 1","pages":"123"},"PeriodicalIF":17.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12670764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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