Pub Date : 2024-10-01DOI: 10.1016/j.expneurol.2024.114981
Stefanie Deininger , Jakob Schumacher , Anna Blechschmidt , Jialei Song , Claudia Klugmann , Gregor Antoniadis , Maria Pedro , Bernd Knöll , Sofia Meyer zu Reckendorf
Peripheral nerve injury (PNI) induces neuroma formation at the severed nerve stump resulting in impaired nerve regeneration and functional recovery in patients. So far, molecular mechanisms and cell types present in the neuroma impeding on regeneration have only sparsely been analyzed. Herein we compare resected human neuroma tissue with intact donor nerves from the same patient. Neuroma from several post-injury timepoints (1–13 months) were included, thereby allowing for temporal correlation with molecular and cellular processes. We observed reduced axonal area and percentage of myelin producing Schwann cells (SCs) compared to intact nerves. However, total SOX10 positive SC numbers were comparable. Notably, markers for SCs in a repair mode including c-JUN, the low-affinity neurotrophin receptor (NTR) p75, SHH (sonic hedgehog) and SC proliferation (phospho-histone H3) were upregulated in neuroma, suggesting presence of SCs in repair status. In agreement, in neuroma, pro-regenerative markers such as phosphorylated i.e. activated CREB (pCREB), ATF3, GAP43 and SCG10 were upregulated. In addition, neuroma tissue was infiltrated by several types of macrophages. Finally, when taken in culture, neuroma SCs were indistinguishable from controls SCs with regard to proliferation and morphology. However, cultured neuroma SCs retained a different molecular signature from control SCs including increased inflammation and reduced gene expression for differentiation markers such as myelin genes.
In summary, human neuroma tissue consists of SCs with a repair status and is infiltrated strongly by several types of macrophages.
{"title":"Nerve injury converts Schwann cells in a long-term repair-like state in human neuroma tissue","authors":"Stefanie Deininger , Jakob Schumacher , Anna Blechschmidt , Jialei Song , Claudia Klugmann , Gregor Antoniadis , Maria Pedro , Bernd Knöll , Sofia Meyer zu Reckendorf","doi":"10.1016/j.expneurol.2024.114981","DOIUrl":"10.1016/j.expneurol.2024.114981","url":null,"abstract":"<div><div>Peripheral nerve injury (PNI) induces neuroma formation at the severed nerve stump resulting in impaired nerve regeneration and functional recovery in patients. So far, molecular mechanisms and cell types present in the neuroma impeding on regeneration have only sparsely been analyzed. Herein we compare resected human neuroma tissue with intact donor nerves from the same patient. Neuroma from several post-injury timepoints (1–13 months) were included, thereby allowing for temporal correlation with molecular and cellular processes. We observed reduced axonal area and percentage of myelin producing Schwann cells (SCs) compared to intact nerves. However, total SOX10 positive SC numbers were comparable. Notably, markers for SCs in a repair mode including c-JUN, the low-affinity neurotrophin receptor (NTR) p75, SHH (sonic hedgehog) and SC proliferation (phospho-histone H3) were upregulated in neuroma, suggesting presence of SCs in repair status. In agreement, in neuroma, pro-regenerative markers such as phosphorylated i.e. activated CREB (pCREB), ATF3, GAP43 and SCG10 were upregulated. In addition, neuroma tissue was infiltrated by several types of macrophages. Finally, when taken in culture, neuroma SCs were indistinguishable from controls SCs with regard to proliferation and morphology. However, cultured neuroma SCs retained a different molecular signature from control SCs including increased inflammation and reduced gene expression for differentiation markers such as myelin genes.</div><div>In summary, human neuroma tissue consists of SCs with a repair status and is infiltrated strongly by several types of macrophages.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114981"},"PeriodicalIF":4.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.expneurol.2024.114983
Tian-Xu Gao , Yu Liang , Jian Li , Dan Zhao , Bai-Jun Dong , Chen Xu , Wei-Dong Zhao , Xia Li , Chuan-Sheng Zhao
Traumatic brain injury (TBI) is a predominant cause of long-term disability in adults, yet the molecular mechanisms underpinning the neuropathological processes associated with it remain inadequately understood. Neutrophil cytosolic factor 1 (NCF1, also known as p47phox) is one of the cytosolic components of NADPH oxidase NOX2. In this study, we observed a reduction in the volume of TBI-induced brain lesions in NCF1-knockout mice compared to controls. Correspondingly, the neuronal loss induced by TBI was mitigated in the NCF1-knockout mice. Behavioral analysis also demonstrated that the motor coordination deficit following TBI was mitigated by the depletion of NCF1. Mechanistically, our findings revealed that NCF1 deficiency attenuated TBI-induced inflammatory responses by inhibiting the release of proinflammatory factors and reducing neutrophil infiltration into the brain parenchyma. Additionally, our results indicated that NCF1 deficiency significantly decreased the levels of reactive oxygen species in neutrophils. Taken together, our findings indicate that NCF1 plays a crucial role in the regulation of brain injury and secondary inflammation post-TBI.
{"title":"Knockout of neutrophil cytosolic factor 1 ameliorates neuroinflammation and motor deficit after traumatic brain injury","authors":"Tian-Xu Gao , Yu Liang , Jian Li , Dan Zhao , Bai-Jun Dong , Chen Xu , Wei-Dong Zhao , Xia Li , Chuan-Sheng Zhao","doi":"10.1016/j.expneurol.2024.114983","DOIUrl":"10.1016/j.expneurol.2024.114983","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is a predominant cause of long-term disability in adults, yet the molecular mechanisms underpinning the neuropathological processes associated with it remain inadequately understood. Neutrophil cytosolic factor 1 (NCF1, also known as p47<sup>phox</sup>) is one of the cytosolic components of NADPH oxidase NOX2. In this study, we observed a reduction in the volume of TBI-induced brain lesions in NCF1-knockout mice compared to controls. Correspondingly, the neuronal loss induced by TBI was mitigated in the NCF1-knockout mice. Behavioral analysis also demonstrated that the motor coordination deficit following TBI was mitigated by the depletion of NCF1. Mechanistically, our findings revealed that NCF1 deficiency attenuated TBI-induced inflammatory responses by inhibiting the release of proinflammatory factors and reducing neutrophil infiltration into the brain parenchyma. Additionally, our results indicated that NCF1 deficiency significantly decreased the levels of reactive oxygen species in neutrophils. Taken together, our findings indicate that NCF1 plays a crucial role in the regulation of brain injury and secondary inflammation post-TBI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114983"},"PeriodicalIF":4.6,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364966","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 : 2024-09-30DOI: 10.1016/j.expneurol.2024.114978
Matt C. Danzi , Eric Powell , Adriana P. Rebelo , Maike F. Dohrn , Danique Beijer , Sarah Fazal , Isaac R.L. Xu , Jessica Medina , Sitong Chen , Yeisha Arcia de Jesus , Jacquelyn Schatzman , Ray E. Hershberger , Mario Saporta , Jonathan Baets , Marni Falk , David N. Herrmann , Steven S. Scherer , Mary M. Reilly , Andrea Cortese , Wilson Marques , Stephan Zuchner
In the past decade, human genetics research saw an acceleration of disease gene discovery and further dissection of the genetic architectures of many disorders. Much of this progress was enabled via data aggregation projects, collaborative data sharing among researchers, and the adoption of sophisticated and standardized bioinformatics analyses pipelines. In 2012, we launched the GENESIS platform, formerly known as GEM.app, with the aims to 1) empower clinical and basic researchers without bioinformatics expertise to analyze and explore genome level data and 2) facilitate the detection of novel pathogenic variation and novel disease genes by leveraging data aggregation and genetic matchmaking. The GENESIS database has grown to over 20,000 datasets from rare disease patients, which were provided by multiple academic research consortia and many individual investigators. Some of the largest global collections of genome-level data are available for Charcot-Marie-Tooth disease, hereditary spastic paraplegia, and cerebellar ataxia. A number of rare disease consortia and networks are archiving their data in this database. Over the past decade, more than 1500 scientists have registered and used this resource and published over 200 papers on gene and variant identifications, which garnered >6000 citations. GENESIS has supported >100 gene discoveries and contributed to approximately half of all gene identifications in the fields of inherited peripheral neuropathies and spastic paraplegia in this time frame. Many diagnostic odysseys of rare disease patients have been resolved. The concept of genomes-to-therapy has borne out for a number of such discoveries that let to rapid clinical trials and expedited natural history studies. This marks GENESIS as one of the most impactful data aggregation initiatives in rare monogenic diseases.
{"title":"The GENESIS database and tools: A decade of discovery in Mendelian genomics","authors":"Matt C. Danzi , Eric Powell , Adriana P. Rebelo , Maike F. Dohrn , Danique Beijer , Sarah Fazal , Isaac R.L. Xu , Jessica Medina , Sitong Chen , Yeisha Arcia de Jesus , Jacquelyn Schatzman , Ray E. Hershberger , Mario Saporta , Jonathan Baets , Marni Falk , David N. Herrmann , Steven S. Scherer , Mary M. Reilly , Andrea Cortese , Wilson Marques , Stephan Zuchner","doi":"10.1016/j.expneurol.2024.114978","DOIUrl":"10.1016/j.expneurol.2024.114978","url":null,"abstract":"<div><div>In the past decade, human genetics research saw an acceleration of disease gene discovery and further dissection of the genetic architectures of many disorders. Much of this progress was enabled via data aggregation projects, collaborative data sharing among researchers, and the adoption of sophisticated and standardized bioinformatics analyses pipelines. In 2012, we launched the GENESIS platform, formerly known as GEM.app, with the aims to 1) empower clinical and basic researchers without bioinformatics expertise to analyze and explore genome level data and 2) facilitate the detection of novel pathogenic variation and novel disease genes by leveraging data aggregation and genetic matchmaking. The GENESIS database has grown to over 20,000 datasets from rare disease patients, which were provided by multiple academic research consortia and many individual investigators. Some of the largest global collections of genome-level data are available for Charcot-Marie-Tooth disease, hereditary spastic paraplegia, and cerebellar ataxia. A number of rare disease consortia and networks are archiving their data in this database. Over the past decade, more than 1500 scientists have registered and used this resource and published over 200 papers on gene and variant identifications, which garnered >6000 citations. GENESIS has supported >100 gene discoveries and contributed to approximately half of all gene identifications in the fields of inherited peripheral neuropathies and spastic paraplegia in this time frame. Many diagnostic odysseys of rare disease patients have been resolved. The concept of genomes-to-therapy has borne out for a number of such discoveries that let to rapid clinical trials and expedited natural history studies. This marks GENESIS as one of the most impactful data aggregation initiatives in rare monogenic diseases.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114978"},"PeriodicalIF":4.6,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364968","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 : 2024-09-30DOI: 10.1016/j.expneurol.2024.114979
Sarah F. McComish , Julia O’Sullivan , Adina Mac Mahon Copas , Magdalena Imiolek , Noreen T. Boyle , Lucy A. Crompton , Jon D. Lane , Maeve A. Caldwell
Astrocytes are the most abundant type of glial cell in the central nervous system and they play pivotal roles in both normal health and disease. Their dysfunction is detrimental to many brain related pathologies. Under pathological conditions, such as Alzheimer's disease, astrocytes adopt an activated reactive phenotype which can contribute to disease progression. A prominent risk factor for many neurodegenerative diseases is neuroinflammation which is the purview of glial cells, such as astrocytes and microglia. Human in vitro models have the potential to reveal relevant disease specific mechanisms, through the study of individual cell types such as astrocytes or the addition of specific factors, such as those secreted by microglia. The aim of this study was to generate human cortical astrocytes, in order to assess their protein and gene expression, examine their reactivity profile in response to exposure to the microglial secreted factors IL-1α, TNFα and C1q and assess their functionality in terms of calcium signalling and metabolism. They successfully differentiate and stimulated reactive astrocytes display increased IL-6, RANTES and GM-CSF secretion, and increased expression of genes associated with reactivity including, IL-6, ICAM1, LCN2, C3 and SERPINA3. Functional assessment of these reactive astrocytes showed a delayed and sustained calcium response to ATP and a concomitant decrease in the expression of connexin–43. Furthermore, it was demonstrated these astrocytes had an increased glycolytic capacity with no effect on oxidative phosphorylation. These findings not only increase our understanding of astrocyte reactivity but also provides a functional platform for drug discovery.
星形胶质细胞是中枢神经系统中最丰富的胶质细胞类型，它们在正常健康和疾病中都发挥着关键作用。星形胶质细胞的功能障碍对许多与大脑有关的病症都是有害的。在阿尔茨海默病等病理条件下，星形胶质细胞会出现活化反应表型，从而导致疾病进展。许多神经退行性疾病的一个突出风险因素是神经炎症，而神经炎症正是星形胶质细胞和小胶质细胞等胶质细胞的职责范围。人类体外模型有可能通过研究星形胶质细胞等单个细胞类型或添加小胶质细胞分泌的特定因子来揭示相关疾病的特定机制。本研究的目的是生成人皮质星形胶质细胞，以评估它们的蛋白质和基因表达，检查它们对小胶质细胞分泌因子 IL-1α、TNFα 和 C1q 的反应谱，并评估它们在钙信号和新陈代谢方面的功能。对这些反应性星形胶质细胞进行的功能评估显示，它们对 ATP 的钙反应延迟且持续，同时连接蛋白-43 的表达也有所下降。此外，研究还表明这些星形胶质细胞的糖酵解能力增强，但对氧化磷酸化没有影响。这些发现不仅增加了我们对星形胶质细胞反应性的了解，还为药物发现提供了一个功能性平台。
{"title":"Reactive astrocytes generated from human iPSC are pro-inflammatory and display altered metabolism","authors":"Sarah F. McComish , Julia O’Sullivan , Adina Mac Mahon Copas , Magdalena Imiolek , Noreen T. Boyle , Lucy A. Crompton , Jon D. Lane , Maeve A. Caldwell","doi":"10.1016/j.expneurol.2024.114979","DOIUrl":"10.1016/j.expneurol.2024.114979","url":null,"abstract":"<div><div>Astrocytes are the most abundant type of glial cell in the central nervous system and they play pivotal roles in both normal health and disease. Their dysfunction is detrimental to many brain related pathologies. Under pathological conditions, such as Alzheimer's disease, astrocytes adopt an activated reactive phenotype which can contribute to disease progression. A prominent risk factor for many neurodegenerative diseases is neuroinflammation which is the purview of glial cells, such as astrocytes and microglia. Human <em>in vitro</em> models have the potential to reveal relevant disease specific mechanisms, through the study of individual cell types such as astrocytes or the addition of specific factors, such as those secreted by microglia. The aim of this study was to generate human cortical astrocytes, in order to assess their protein and gene expression, examine their reactivity profile in response to exposure to the microglial secreted factors IL-1α, TNFα and C1q and assess their functionality in terms of calcium signalling and metabolism. They successfully differentiate and stimulated reactive astrocytes display increased IL-6, RANTES and GM-CSF secretion, and increased expression of genes associated with reactivity including, <em>IL-6</em>, <em>ICAM1</em>, <em>LCN2</em>, <em>C3</em> and <em>SERPINA3</em>. Functional assessment of these reactive astrocytes showed a delayed and sustained calcium response to ATP and a concomitant decrease in the expression of connexin–43. Furthermore, it was demonstrated these astrocytes had an increased glycolytic capacity with no effect on oxidative phosphorylation. These findings not only increase our understanding of astrocyte reactivity but also provides a functional platform for drug discovery.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114979"},"PeriodicalIF":4.6,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364967","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 : 2024-09-30DOI: 10.1016/j.expneurol.2024.114977
Shengqiang Xie , Hanbo Zhang , Gang Cheng , Bingxian Wang , Yanteng Li , Xiaowen Xing , Cui Wang , Mengwen Song , Zengqiang Yuan , Zhiqiang Liu , Jianning Zhang
Traumatic brain injury (TBI) is a major cause of death and disability worldwide, with its severity potentially exacerbated by seawater immersion. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has been implicated in TBI pathogenesis. However, the specific occurrence and underlying mechanisms of ferroptosis in the context of TBI compounded by seawater immersion remain unclear. Subsequently, we investigated the effects of seawater immersion on ferroptosis after the application of deferoxamine (DFO), an iron chelator and ferroptosis inhibitor, to explore its potential therapeutic value. We conducted RNA sequencing, protein expression analysis, oxidative stress assessment, histopathological examination, and behavioral testing to comprehensively evaluate the impact of DFO on ferroptosis and neurological outcomes. Our results demonstrated that seawater immersion significantly exacerbated ferroptosis in TBI. DFO treatment, however, attenuated ferroptosis, alleviated oxidative stress, reduced brain tissue damage, improved neuronal survival, and promoted motor function recovery. Despite these benefits, DFO exhibited limited effects on anxiety, novel object recognition, and spatial learning and memory. These findings suggest that ferroptosis represents a novel pathological mechanism in TBI under seawater immersion, and that DFO is a promising neuroprotective agent capable of modulating ferroptosis and enhancing neurological function. This study offers new insights into the complex injury conditions associated with TBI and seawater immersion, highlighting the potential of targeting ferroptosis for therapeutic intervention.
{"title":"Deferoxamine alleviates ferroptosis in seawater immersion combined with traumatic brain injury","authors":"Shengqiang Xie , Hanbo Zhang , Gang Cheng , Bingxian Wang , Yanteng Li , Xiaowen Xing , Cui Wang , Mengwen Song , Zengqiang Yuan , Zhiqiang Liu , Jianning Zhang","doi":"10.1016/j.expneurol.2024.114977","DOIUrl":"10.1016/j.expneurol.2024.114977","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is a major cause of death and disability worldwide, with its severity potentially exacerbated by seawater immersion. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has been implicated in TBI pathogenesis. However, the specific occurrence and underlying mechanisms of ferroptosis in the context of TBI compounded by seawater immersion remain unclear. Subsequently, we investigated the effects of seawater immersion on ferroptosis after the application of deferoxamine (DFO), an iron chelator and ferroptosis inhibitor, to explore its potential therapeutic value. We conducted RNA sequencing, protein expression analysis, oxidative stress assessment, histopathological examination, and behavioral testing to comprehensively evaluate the impact of DFO on ferroptosis and neurological outcomes. Our results demonstrated that seawater immersion significantly exacerbated ferroptosis in TBI. DFO treatment, however, attenuated ferroptosis, alleviated oxidative stress, reduced brain tissue damage, improved neuronal survival, and promoted motor function recovery. Despite these benefits, DFO exhibited limited effects on anxiety, novel object recognition, and spatial learning and memory. These findings suggest that ferroptosis represents a novel pathological mechanism in TBI under seawater immersion, and that DFO is a promising neuroprotective agent capable of modulating ferroptosis and enhancing neurological function. This study offers new insights into the complex injury conditions associated with TBI and seawater immersion, highlighting the potential of targeting ferroptosis for therapeutic intervention.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114977"},"PeriodicalIF":4.6,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364965","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 : 2024-09-29DOI: 10.1016/j.expneurol.2024.114980
Stefano Casarin , Nele A. Haelterman , Keren Machol
Artificial intelligence (AI) has the potential to revolutionize chronic pain management by guiding the development of effective treatment strategies that are tailored to individual patient needs. This potential comes from AI's ability to analyze large and heterogeneous datasets to identify hidden patterns. When applied to clinical datasets of a particular patient population, AI can be used to identify pain subtypes among patients, predict treatment responses, and guide the clinical decision-making process. However, integrating AI into the clinical practice requires overcoming challenges such as data quality, the complexity of human pain physiology, and validation against diverse patient populations. Targeted, collaborative efforts among clinicians, researchers, and AI specialists will be needed to maximize AI's capabilities and advance current management and treatment of chronic pain conditions.
{"title":"Transforming personalized chronic pain management with artificial intelligence: A commentary on the current landscape and future directions","authors":"Stefano Casarin , Nele A. Haelterman , Keren Machol","doi":"10.1016/j.expneurol.2024.114980","DOIUrl":"10.1016/j.expneurol.2024.114980","url":null,"abstract":"<div><div>Artificial intelligence (AI) has the potential to revolutionize chronic pain management by guiding the development of effective treatment strategies that are tailored to individual patient needs. This potential comes from AI's ability to analyze large and heterogeneous datasets to identify hidden patterns. When applied to clinical datasets of a particular patient population, AI can be used to identify pain subtypes among patients, predict treatment responses, and guide the clinical decision-making process. However, integrating AI into the clinical practice requires overcoming challenges such as data quality, the complexity of human pain physiology, and validation against diverse patient populations. Targeted, collaborative efforts among clinicians, researchers, and AI specialists will be needed to maximize AI's capabilities and advance current management and treatment of chronic pain conditions.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114980"},"PeriodicalIF":4.6,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-29DOI: 10.1016/j.expneurol.2024.114982
Shu-Qin Ding , Hua-Zheng Yan , Jian-Xiong Gao , Yu-Qing Chen , Nan Zhang , Rui Wang , Jiang-Yan Li , Jian-Guo Hu , He-Zuo Lü
Apoptosis associated speck like protein containing a card (ASC), the key adaptor protein of the assembly and activation of canonical inflammasomes, has been found to play a significant role in neuroinflammation after spinal cord injury (SCI). The previous studies indicated that widely block or knockout ASC can ameliorate SCI. However, ASC is ubiquitously expressed in infiltrated macrophages and local microglia, so further exploration is needed on which type of cell playing the key role. In this study, using the LysMcre;Ascflox/flox mice with macrophage-specifc ASC conditional knockout (CKO) and contusive SCI model, we focus on evaluating the specific role of ASC in lysozyme 2 (LysM)+ myeloid cells (mainly infiltrated macrophages) in this pathology. The results revealed that macrophage-specifc Asc CKO exhibited the follow effects: (1) A significant reduction in the numbers of infiltrated macrophages in the all phases of SCI, and activated microglia in the acute and subacute phases. (2) A significant reduction in ASC, caspase-1, interleukin (IL)-1β, and IL-18 compared to control mice. (3) In the acute and subacute phases of SCI, M1 subset differentiation was inhibited, and M2 differentiation was increased. (4) Histology and hindlimb motor recoveries were improved. In conclusion, this study elucidates that macrophage-specific ASC CKO can improve nerve function recovery after SCI by regulating M1/M2 polarization through inhibiting ASC-dependent inflammasome signaling axis. This indicates that ASC in peripheral infiltrated macrophages may play an important role in SCI pathology, at least in mice, could be a potential target for treatment.
{"title":"Genetic deletion of the apoptosis associated speck like protein containing a card in LysM+ macrophages attenuates spinal cord injury by regulating M1/M2 polarization through ASC-dependent inflammasome signaling axis","authors":"Shu-Qin Ding , Hua-Zheng Yan , Jian-Xiong Gao , Yu-Qing Chen , Nan Zhang , Rui Wang , Jiang-Yan Li , Jian-Guo Hu , He-Zuo Lü","doi":"10.1016/j.expneurol.2024.114982","DOIUrl":"10.1016/j.expneurol.2024.114982","url":null,"abstract":"<div><div>Apoptosis associated speck like protein containing a card (ASC), the key adaptor protein of the assembly and activation of canonical inflammasomes, has been found to play a significant role in neuroinflammation after spinal cord injury (SCI). The previous studies indicated that widely block or knockout ASC can ameliorate SCI. However, ASC is ubiquitously expressed in infiltrated macrophages and local microglia, so further exploration is needed on which type of cell playing the key role. In this study, using the LysM<sup>cre</sup>;Asc<sup>flox/flox</sup> mice with macrophage-specifc ASC conditional knockout (CKO) and contusive SCI model, we focus on evaluating the specific role of ASC in lysozyme 2 (LysM)<sup>+</sup> myeloid cells (mainly infiltrated macrophages) in this pathology. The results revealed that macrophage-specifc Asc CKO exhibited the follow effects: (1) A significant reduction in the numbers of infiltrated macrophages in the all phases of SCI, and activated microglia in the acute and subacute phases. (2) A significant reduction in ASC, caspase-1, interleukin (IL)-1β, and IL-18 compared to control mice. (3) In the acute and subacute phases of SCI, M1 subset differentiation was inhibited, and M2 differentiation was increased. (4) Histology and hindlimb motor recoveries were improved. In conclusion, this study elucidates that macrophage-specific ASC CKO can improve nerve function recovery after SCI by regulating M1/M2 polarization through inhibiting ASC-dependent inflammasome signaling axis. This indicates that ASC in peripheral infiltrated macrophages may play an important role in SCI pathology, at least in mice, could be a potential target for treatment.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114982"},"PeriodicalIF":4.6,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364970","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 : 2024-09-28DOI: 10.1016/j.expneurol.2024.114976
Laurie K. Bale , Sally A. West , Naomi M. Gades , Darren J. Baker , Cheryl A. Conover
Alzheimer's disease (AD) is a progressive neurodegenerative disease of age with no effective preventative or treatment approaches. Deeper understanding of the mechanisms underlying the accumulation of toxic β-amyloid oligopeptides and the formation of amyloid plaque in AD has the potential to identify new therapeutic targets. Prior research links the insulin-like growth factor (IGF) system to pathologic mechanisms underlying AD. Suppression of local IGF-I receptor (IGFIR) signaling in AD mice has been shown to reduce plaque formation in the brain and delay neurodegeneration and behavioral changes. However, direct inhibitors of IGFIR signaling are not a viable treatment option for AD due to the essentiality of the IGFIR in physiological growth and metabolism. We have previously demonstrated a more selective means to reduce local IGFIR signaling through inhibition of PAPP-A, a novel zinc metalloprotease that regulates local IGF-I bioavailability through cleavage of inhibitory IGF binding proteins. Here we tested if deletion of PAPP-A in a mouse model of AD provides protection against pathology and behavioral changes. We show that compared to AD mice, AD/PAPP-A KO mice had significantly less plaque burden, reduced astrocytic activation, decreased IGF-IR activity, and improved cognition. Human senile AD plaques showed specific immunostaining for PAPP-A. Thus, inhibition of PAPP-A expression or activity may represent a novel treatment strategy for AD.
阿尔茨海默病（AD）是一种渐进性老年神经退行性疾病，目前尚无有效的预防或治疗方法。深入了解 AD 中有毒的 β 淀粉样蛋白寡肽的积累和淀粉样斑块的形成机制，有可能发现新的治疗靶点。先前的研究将胰岛素样生长因子（IGF）系统与AD的病理机制联系起来。研究表明，抑制AD小鼠的局部IGF-I受体（IGFIR）信号传导可减少大脑中斑块的形成，延缓神经变性和行为改变。然而，由于 IGFIR 在生理生长和新陈代谢中的重要作用，IGFIR 信号的直接抑制剂并不是治疗 AD 的可行方案。我们之前通过抑制 PAPP-A（一种新型锌金属蛋白酶，可通过裂解抑制性 IGF 结合蛋白调节局部 IGF-I 的生物利用度）证明了一种更具选择性的减少局部 IGFIR 信号传导的方法。在这里，我们测试了在 AD 小鼠模型中删除 PAPP-A 是否能保护小鼠免受病理和行为变化的影响。我们发现，与注意力缺失症小鼠相比，AD/PAPP-A KO 小鼠的斑块负担明显减轻，星形胶质细胞活化减少，IGF-IR 活性降低，认知能力提高。人类老年 AD 斑块显示出 PAPP-A 的特异性免疫染色。因此，抑制PAPP-A的表达或活性可能是治疗AD的一种新策略。
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Pub Date : 2024-09-25DOI: 10.1016/j.expneurol.2024.114965
P.T.J.A. Williams , Eva Schelbaum , Chaimae Ahmanna , Heather Alexander , Kadia Kanté , Sylvia Soares , Hisham Sharif , Fatiha Nothias , John H. Martin
Spinal cord injury (SCI) damages the trauma site, leading to progressive and secondary structural defects rostral and caudal to the injury. Interruption of ascending and descending pathways produce motor, sensory, and autonomic impairments, driving the need for effective therapies. In this study, we address lesion site repair and promoting descending projections using a combined biomaterial-neuromodulation strategy in a rat model of cervical contusion SCI. To promote tissue repair, we used Chitosan fragmented physical hydrogel suspension (Cfphs), a biomaterial formulation optimized to mitigate inflammation and support tissue remodeling. To promote descending projections, we targeted the corticospinal motor system with dual motor cortex–trans-spinal direct current neuromodulation to promote spared corticospinal tract (CST) axon sprouting rostral and caudal to SCI. Cfphs, injected into the lesion site acutely, was followed by 10 days of daily neuromodulation. Analysis was made at the chronic phase, 8-weeks post-SCI. Compared with SCI only, Cfphs alone or in combination with neuromodulation prevented cavity formation, by promoting tissue remodeling at the injury site, abrogated astrogliosis surrounding the newly formed tissue, and enabled limited CST axon growth into the remodeled injury site. Cfphs alone significantly reduced CST axon dieback and was accompanied by preserving more CST axon gray matter projections rostral to SCI. Cfphs + neuromodulation produced sprouting rostral and caudal to injury. Our findings show that our novel biomaterial-neuromodulation combinatorial strategy achieves significant injury site tissue remodeling and promoted CST projections rostral and caudal to SCI.
{"title":"Combined biomaterial scaffold and neuromodulation strategy to promote tissue repair and corticospinal connectivity after spinal cord injury in a rodent model","authors":"P.T.J.A. Williams , Eva Schelbaum , Chaimae Ahmanna , Heather Alexander , Kadia Kanté , Sylvia Soares , Hisham Sharif , Fatiha Nothias , John H. Martin","doi":"10.1016/j.expneurol.2024.114965","DOIUrl":"10.1016/j.expneurol.2024.114965","url":null,"abstract":"<div><div>Spinal cord injury (SCI) damages the trauma site, leading to progressive and secondary structural defects rostral and caudal to the injury. Interruption of ascending and descending pathways produce motor, sensory, and autonomic impairments, driving the need for effective therapies. In this study, we address lesion site repair and promoting descending projections using a combined biomaterial-neuromodulation strategy in a rat model of cervical contusion SCI. To promote tissue repair, we used Chitosan fragmented physical hydrogel suspension (C<sub>fphs</sub>), a biomaterial formulation optimized to mitigate inflammation and support tissue remodeling. To promote descending projections, we targeted the corticospinal motor system with dual motor cortex–trans-spinal direct current neuromodulation to promote spared corticospinal tract (CST) axon sprouting rostral and caudal to SCI. C<sub>fphs</sub>, injected into the lesion site acutely, was followed by 10 days of daily neuromodulation. Analysis was made at the chronic phase, 8-weeks post-SCI. Compared with SCI only, C<sub>fphs</sub> alone or in combination with neuromodulation prevented cavity formation, by promoting tissue remodeling at the injury site, abrogated astrogliosis surrounding the newly formed tissue, and enabled limited CST axon growth into the remodeled injury site. C<sub>fphs</sub> alone significantly reduced CST axon dieback and was accompanied by preserving more CST axon gray matter projections rostral to SCI. C<sub>fphs</sub> + neuromodulation produced sprouting rostral and caudal to injury. Our findings show that our novel biomaterial-neuromodulation combinatorial strategy achieves significant injury site tissue remodeling and promoted CST projections rostral and caudal to SCI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114965"},"PeriodicalIF":4.6,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344418","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 : 2024-09-25DOI: 10.1016/j.expneurol.2024.114969
Jennaya Christensen , Elaina Vlassopoulos , Christopher K. Barlow , Ralf B. Schittenhelm , Crystal N. Li , Marissa Sgro , Samantha Warren , Bridgette D. Semple , Glenn R. Yamakawa , Sandy R. Shultz , Richelle Mychasiuk
The sleep-wake cycle plays an influential role in the development and progression of repeat mild traumatic brain injury (RmTBI)-related pathology. Therefore, we first aimed to manipulate the sleep-wake cycle post-RmTBI using modafinil, a wake-promoting substance used for the treatment of narcolepsy. We hypothesized that modafinil would exacerbate RmTBI-induced deficits. Chronic behavioural analyses were completed along with a 27-plex serum cytokine array, metabolomic and proteomic analyses of cerebrospinal fluid (CSF), as well as immunohistochemical staining in structures important for sleep/wake cycles, to examine orexin, melanin-concentrating hormone, tyrosine hydroxylase, and choline acetyltransferase, in the lateral hypothalamus, locus coeruleus, and basal forebrain, respectively. Contrary to expectation, modafinil administration attenuated behavioural deficits, metabolomic changes, and neuropathological modifications. Therefore, the second aim was to determine if the beneficial effects of modafinil treatment were driven by the orexinergic system. The same experimental protocol was used; however, RmTBI rats received chronic orexin-A administration instead of modafinil. Orexin-A administration produced drastically different outcomes, exacerbating anxiety-related and motor deficits, while also significantly disrupting their metabolomic and neuropathological profiles. These results suggest that the beneficial effects of modafinil administration post-RmTBI, work independently of its wake-promoting properties, as activation of the orexinergic wake-promoting system with orexin-A was detrimental. Overall, these findings highlight the complexity of sleep-wake changes in the injured brain and showcase the potential of the arousal and sleep systems in its treatment.
{"title":"The beneficial effects of modafinil administration on repeat mild traumatic brain injury (RmTBI) pathology in adolescent male rats are not dependent upon the orexinergic system","authors":"Jennaya Christensen , Elaina Vlassopoulos , Christopher K. Barlow , Ralf B. Schittenhelm , Crystal N. Li , Marissa Sgro , Samantha Warren , Bridgette D. Semple , Glenn R. Yamakawa , Sandy R. Shultz , Richelle Mychasiuk","doi":"10.1016/j.expneurol.2024.114969","DOIUrl":"10.1016/j.expneurol.2024.114969","url":null,"abstract":"<div><div>The sleep-wake cycle plays an influential role in the development and progression of repeat mild traumatic brain injury (RmTBI)-related pathology. Therefore, we first aimed to manipulate the sleep-wake cycle post-RmTBI using modafinil, a wake-promoting substance used for the treatment of narcolepsy. We hypothesized that modafinil would exacerbate RmTBI-induced deficits. Chronic behavioural analyses were completed along with a 27-plex serum cytokine array, metabolomic and proteomic analyses of cerebrospinal fluid (CSF), as well as immunohistochemical staining in structures important for sleep/wake cycles, to examine orexin, melanin-concentrating hormone, tyrosine hydroxylase, and choline acetyltransferase, in the lateral hypothalamus, locus coeruleus, and basal forebrain, respectively. Contrary to expectation, modafinil administration attenuated behavioural deficits, metabolomic changes, and neuropathological modifications. Therefore, the second aim was to determine if the beneficial effects of modafinil treatment were driven by the orexinergic system. The same experimental protocol was used; however, RmTBI rats received chronic orexin-A administration instead of modafinil. Orexin-A administration produced drastically different outcomes, exacerbating anxiety-related and motor deficits, while also significantly disrupting their metabolomic and neuropathological profiles. These results suggest that the beneficial effects of modafinil administration post-RmTBI, work independently of its wake-promoting properties, as activation of the orexinergic wake-promoting system with orexin-A was detrimental. Overall, these findings highlight the complexity of sleep-wake changes in the injured brain and showcase the potential of the arousal and sleep systems in its treatment.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114969"},"PeriodicalIF":4.6,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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