Pub Date : 2024-08-10DOI: 10.1016/j.nbd.2024.106635
Early-onset epilepsy following ischemic stroke is a severe neurological condition, the pathogenesis of which remains incompletely understood. Recent studies suggest that Neural stem/progenitor cells (NSPCs) play a crucial role in the disease process, yet the precise molecular mechanisms regulating NSPCs have not been thoroughly investigated. This study utilized single-cell transcriptome sequencing and bioinformatics analysis to identify disease-related genes, which were subsequently validated in both in vitro and in vivo experiments. The findings revealed that Hsp90aa1 (heat shock protein 90 kDa alpha, class A member 1), Jun proto-oncogene (JUN), and CC Motif Ligation 2 (Ccl2) constitute an important regulatory axis influencing the migration and differentiation of NSPCs, potentially impacting the onset and progression of early-onset epilepsy post-ischemic stroke. Additionally, the expression of Hsp90aa1 was found to influence the likelihood of seizure occurrence and the severity of brain ischemia.
{"title":"Hsp90aa1/JUN/Ccl2 regulatory axis mediates migration and differentiation of NSPCs, promoting the onset and progression of early post-ischemic stroke epilepsy","authors":"","doi":"10.1016/j.nbd.2024.106635","DOIUrl":"10.1016/j.nbd.2024.106635","url":null,"abstract":"<div><p>Early-onset epilepsy following ischemic stroke is a severe neurological condition, the pathogenesis of which remains incompletely understood. Recent studies suggest that Neural stem/progenitor cells (NSPCs) play a crucial role in the disease process, yet the precise molecular mechanisms regulating NSPCs have not been thoroughly investigated. This study utilized single-cell transcriptome sequencing and bioinformatics analysis to identify disease-related genes, which were subsequently validated in both <em>in vitro</em> and <em>in vivo</em> experiments. The findings revealed that Hsp90aa1 (heat shock protein 90 kDa alpha, class A member 1), Jun proto-oncogene (JUN), and C<img>C Motif Ligation 2 (Ccl2) constitute an important regulatory axis influencing the migration and differentiation of NSPCs, potentially impacting the onset and progression of early-onset epilepsy post-ischemic stroke. Additionally, the expression of Hsp90aa1 was found to influence the likelihood of seizure occurrence and the severity of brain ischemia.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002353/pdfft?md5=db9dcab707c1cc71cab29960ae4ef014&pid=1-s2.0-S0969996124002353-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141917186","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 : 2024-08-08DOI: 10.1016/j.nbd.2024.106626
The kidney-brain axis is a bidirectional communication network connecting the kidneys and the brain, potentially affected by inflammation, uremic toxin, vascular injury, neuronal degeneration, and so on, leading to a range of diseases. Numerous studies emphasize the disruptions of the kidney-brain axis may contribute to the high morbidity of neurological disorders, such as cognitive impairment (CI) in the natural course of chronic kidney disease (CKD). Although the pathophysiology of the kidney-brain axis has not been fully elucidated, epidemiological data indicate that patients at all stages of CKD have a higher risk of developing CI compared with the general population. In contrast to other reviews, we mentioned some commonly used medicines in CKD that may play a pivotal role in the pathogenesis of CI. Revealing the pathophysiology interactions between kidney damage and brain function can reduce the potential risk of future CI. This review will deeply explore the characteristics, indicators, and potential pathophysiological mechanisms of CKD-related CI. It will provide a theoretical basis for identifying CI that progresses during CKD and ultimately prevents and treats CKD-related CI.
肾-脑轴是连接肾脏和大脑的双向交流网络,可能受到炎症、尿毒症毒素、血管损伤、神经元变性等因素的影响,导致一系列疾病。大量研究强调,肾脑轴的破坏可能是慢性肾脏病(CKD)自然病程中认知障碍(CI)等神经系统疾病高发病率的原因之一。虽然肾-脑轴的病理生理学尚未完全阐明,但流行病学数据表明,与普通人群相比,处于 CKD 各个阶段的患者罹患 CI 的风险都较高。与其他综述不同的是,我们提到了一些 CKD 的常用药物,它们可能在 CI 的发病机制中起着关键作用。揭示肾脏损伤与脑功能之间的病理生理学相互作用可降低未来罹患 CI 的潜在风险。本综述将深入探讨 CKD 相关 CI 的特征、指标和潜在病理生理机制。它将为识别 CKD 期间进展的 CI 并最终预防和治疗 CKD 相关 CI 提供理论依据。
{"title":"Kidney-brain axis in the pathogenesis of cognitive impairment","authors":"","doi":"10.1016/j.nbd.2024.106626","DOIUrl":"10.1016/j.nbd.2024.106626","url":null,"abstract":"<div><p>The kidney-brain axis is a bidirectional communication network connecting the kidneys and the brain, potentially affected by inflammation, uremic toxin, vascular injury, neuronal degeneration, and so on, leading to a range of diseases. Numerous studies emphasize the disruptions of the kidney-brain axis may contribute to the high morbidity of neurological disorders, such as cognitive impairment (CI) in the natural course of chronic kidney disease (CKD). Although the pathophysiology of the kidney-brain axis has not been fully elucidated, epidemiological data indicate that patients at all stages of CKD have a higher risk of developing CI compared with the general population. In contrast to other reviews, we mentioned some commonly used medicines in CKD that may play a pivotal role in the pathogenesis of CI. Revealing the pathophysiology interactions between kidney damage and brain function can reduce the potential risk of future CI. This review will deeply explore the characteristics, indicators, and potential pathophysiological mechanisms of CKD-related CI. It will provide a theoretical basis for identifying CI that progresses during CKD and ultimately prevents and treats CKD-related CI.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002262/pdfft?md5=41674270a8ec86330f034b2c3c59b57b&pid=1-s2.0-S0969996124002262-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913403","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 : 2024-08-07DOI: 10.1016/j.nbd.2024.106634
Thrombospondins (TSPs) are astrocyte-secreted extracellular matrix proteins that play key roles as regulators of synaptogenesis in the central nervous system. We previously showed that TSP1/2 are upregulated in the partial neocortical isolation model (“undercut” or “UC” below) of posttraumatic epileptogenesis and may contribute to abnormal axonal sprouting, aberrant synaptogenesis and epileptiform discharges in the UC cortex. These results led to the hypothesis that posttraumatic epileptogeneis would be reduced in TSP1/2 knockout (TSP1/2 KO) mice. To test the hypothesis, we made UC lesions at P21, and subsequent experiments were conducted 14d later at P35. Ex vivo extracellular single or multi-electrode field potential recordings were obtained from layer V in cortical slices at P35 and in vivo video-EEGs of spontaneous epileptiform bursts were recorded to examine the effect of TSP1/2 deletion on epileptogenesis following cortical injury. Immunohistochemical experiments were performed to assess the effect of TSP1/2 KO + UC on the number of putative excitatory synapses and the expression of TSP4 and HEVIN, other astrocytic proteins known to up-regulate excitatory synapse formation. Unexpectedly, our results showed that, compared with WT + UC mice, TSP1/2 KO + UC mice displayed increased epileptiform activity, as indicated by 1) increased incidence and more rapid propagation of evoked and spontaneous epileptiform discharges in UC neocortical slices; 2) increased occurrence of spontaneous epileptiform discharges in vivo. There was an associated increase in the density of VLUT1/PSD95-IR colocalizations (putative excitatory synapses) and significantly upregulated TSP4- and HEVIN-IR in TSP1/2 KO + UC versus WT + UC mice. Results suggest that TSP1/2 deletion plays a potential epileptogenic role following neocortical injury, associated with compensatory upregulation of TSP4 and HEVIN, which may contribute to the increase in the density of excitatory synapses and resulting neural network hyperexcitability.
{"title":"Increased excitatory connectivity and epileptiform activity in thrombospondin1/2 knockout mice following cortical trauma","authors":"","doi":"10.1016/j.nbd.2024.106634","DOIUrl":"10.1016/j.nbd.2024.106634","url":null,"abstract":"<div><p>Thrombospondins (TSPs) are astrocyte-secreted extracellular matrix proteins that play key roles as regulators of synaptogenesis in the central nervous system. We previously showed that TSP1/2 are upregulated in the partial neocortical isolation model (“undercut” or “UC” below) of posttraumatic epileptogenesis and may contribute to abnormal axonal sprouting, aberrant synaptogenesis and epileptiform discharges in the UC cortex. These results led to the hypothesis that posttraumatic epileptogeneis would be reduced in TSP1/2 knockout (TSP1/2 KO) mice. To test the hypothesis, we made UC lesions at P21, and subsequent experiments were conducted 14d later at P35. Ex vivo extracellular single or multi-electrode field potential recordings were obtained from layer V in cortical slices at P35 and in vivo video-EEGs of spontaneous epileptiform bursts were recorded to examine the effect of TSP1/2 deletion on epileptogenesis following cortical injury. Immunohistochemical experiments were performed to assess the effect of TSP1/2 KO + UC on the number of putative excitatory synapses and the expression of TSP4 and HEVIN, other astrocytic proteins known to up-regulate excitatory synapse formation. Unexpectedly, our results showed that, compared with WT + UC mice, TSP1/2 KO + UC mice displayed increased epileptiform activity, as indicated by 1) increased incidence and more rapid propagation of evoked and spontaneous epileptiform discharges in UC neocortical slices; 2) increased occurrence of spontaneous epileptiform discharges in vivo. There was an associated increase in the density of VLUT1/PSD95-IR colocalizations (putative excitatory synapses) and significantly upregulated TSP4- and HEVIN-IR in TSP1/2 KO + UC versus WT + UC mice. Results suggest that TSP1/2 deletion plays a potential epileptogenic role following neocortical injury, associated with compensatory upregulation of TSP4 and HEVIN, which may contribute to the increase in the density of excitatory synapses and resulting neural network hyperexcitability.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002341/pdfft?md5=3117d371b0ea086e6bf54568adb042a3&pid=1-s2.0-S0969996124002341-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913402","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 : 2024-08-06DOI: 10.1016/j.nbd.2024.106625
C-terminus of HSP70 interacting protein (CHIP) is an E3 ubiquitin ligase and HSP70 cochaperone. Mutations in the CHIP encoding gene are the cause of two neurodegenerative conditions: spinocerebellar ataxia autosomal dominant type 48 (SCA48) and autosomal recessive type 16 (SCAR16). The mechanisms underlying CHIP-associated diseases are currently unknown. Mitochondrial dysfunction, specifically dysfunction in mitochondrial autophagy (mitophagy), is increasingly implicated in neurodegenerative diseases and loss of CHIP has been demonstrated to result in mitochondrial dysfunction in multiple animal models, although how CHIP is involved in mitophagy regulation has been previously unknown. Here, we demonstrate that CHIP acts as a negative regulator of the PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy pathway, promoting the degradation of PINK1, impairing Parkin translocation to the mitochondria, and suppressing mitophagy in response to mitochondrial stress. We also show that loss of CHIP enhances neuronal mitophagy in a PINK1 and Parkin dependent manner in Caenorhabditis elegans. Furthermore, we find that multiple disease-associated mutations in CHIP dysregulate mitophagy both in vitro and in vivo in C. elegans neurons, a finding which could implicate mitophagy dysregulation in CHIP-associated diseases.
{"title":"Disease-associated mutations in C-terminus of HSP70 interacting protein (CHIP) impair its ability to negatively regulate mitophagy","authors":"","doi":"10.1016/j.nbd.2024.106625","DOIUrl":"10.1016/j.nbd.2024.106625","url":null,"abstract":"<div><p>C-terminus of HSP70 interacting protein (CHIP) is an E3 ubiquitin ligase and HSP70 cochaperone. Mutations in the CHIP encoding gene are the cause of two neurodegenerative conditions: spinocerebellar ataxia autosomal dominant type 48 (SCA48) and autosomal recessive type 16 (SCAR16). The mechanisms underlying CHIP-associated diseases are currently unknown. Mitochondrial dysfunction, specifically dysfunction in mitochondrial autophagy (mitophagy), is increasingly implicated in neurodegenerative diseases and loss of CHIP has been demonstrated to result in mitochondrial dysfunction in multiple animal models, although how CHIP is involved in mitophagy regulation has been previously unknown. Here, we demonstrate that CHIP acts as a negative regulator of the PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy pathway, promoting the degradation of PINK1, impairing Parkin translocation to the mitochondria, and suppressing mitophagy in response to mitochondrial stress. We also show that loss of CHIP enhances neuronal mitophagy in a PINK1 and Parkin dependent manner in <em>Caenorhabditis elegans</em>. Furthermore, we find that multiple disease-associated mutations in CHIP dysregulate mitophagy both <em>in vitro</em> and <em>in vivo</em> in <em>C. elegans</em> neurons, a finding which could implicate mitophagy dysregulation in CHIP-associated diseases.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002250/pdfft?md5=18efc96eebe8e6e1c402325bba9254b4&pid=1-s2.0-S0969996124002250-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907174","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 : 2024-08-06DOI: 10.1016/j.nbd.2024.106633
The triggers of status epilepticus (SE) in non-epileptic patients can vary widely, from idiopathic causes to exposure to chemoconvulsants. Regardless of its etiology, prolonged SE can cause significant brain damage, commonly resulting in the development of epilepsy, which is often accompanied by increased anxiety. GABAA receptor (GABAAR)-mediated inhibition has a central role among the mechanisms underlying brain damage and the ensuing epilepsy and anxiety. During SE, calcium influx primarily via ionotropic glutamate receptors activates signaling cascades which trigger a rapid internalization of synaptic GABAARs; this weakens inhibition, exacerbating seizures and excitotoxicity. GABAergic interneurons are more susceptible to excitotoxic death than principal neurons. During the latent period of epileptogenesis, the aberrant reorganization in synaptic interactions that follow interneuronal loss in injured brain regions, leads to the formation of hyperexcitable, seizurogenic neuronal circuits, along with disturbances in brain oscillatory rhythms. Reduction in the spontaneous, rhythmic “bursts” of IPSCs in basolateral amygdala neurons is likely to play a central role in anxiogenesis. Protecting interneurons during SE is key to preventing both epilepsy and anxiety. Antiglutamatergic treatments, including antagonism of calcium-permeable AMPA receptors, can be expected to control seizures and reduce excitotoxicity not only by directly suppressing hyperexcitation, but also by counteracting the internalization of synaptic GABAARs. Benzodiazepines, as delayed treatment of SE, have low efficacy due to the reduction and dispersion of their targets (the synaptic GABAARs), but also because themselves contribute to further reduction of available GABAARs at the synapse; furthermore, benzodiazepines may be completely ineffective in the immature brain.
非癫痫患者出现癫痫状态(SE)的诱因千差万别,从特发性原因到接触化学惊厥剂。无论其病因如何,长时间的癫痫状态都会造成严重的脑损伤,通常会导致癫痫的发生,并常常伴有焦虑加重。GABAA 受体(GABAAR)介导的抑制作用在脑损伤及随之而来的癫痫和焦虑的基本机制中起着核心作用。在 SE 期间,钙流入主要通过离子型谷氨酸受体激活信号级联,从而引发突触 GABAARs 快速内化;这会削弱抑制作用,加剧癫痫发作和兴奋毒性。GABA 能中间神经元比主神经元更容易受到兴奋性毒性的影响而死亡。在癫痫发生的潜伏期,受伤脑区的神经元间丧失后,突触相互作用会发生异常重组,从而形成过度兴奋的癫痫源神经元回路,同时扰乱大脑振荡节奏。杏仁核基底外侧神经元中自发的、有节奏的 "突发 "IPSCs的减少很可能在焦虑发生过程中起着核心作用。在 SE 期间保护中间神经元是预防癫痫和焦虑的关键。抗谷氨酸能治疗(包括拮抗钙离子渗透性 AMPA 受体)不仅能直接抑制过度兴奋,还能抵消突触 GABAARs 的内化,从而有望控制癫痫发作并减少兴奋毒性。苯二氮卓类药物作为 SE 的延迟治疗药物,由于其靶点(突触 GABAARs)的减少和分散而疗效不佳,而且其本身也会导致突触处可用 GABAARs 的进一步减少;此外,苯二氮卓类药物在未成熟的大脑中可能完全无效。
{"title":"Alterations in GABAA receptor-mediated inhibition triggered by status epilepticus and their role in epileptogenesis and increased anxiety","authors":"","doi":"10.1016/j.nbd.2024.106633","DOIUrl":"10.1016/j.nbd.2024.106633","url":null,"abstract":"<div><p>The triggers of status epilepticus (SE) in non-epileptic patients can vary widely, from idiopathic causes to exposure to chemoconvulsants. Regardless of its etiology, prolonged SE can cause significant brain damage, commonly resulting in the development of epilepsy, which is often accompanied by increased anxiety. GABA<sub>A</sub> receptor (GABA<sub>A</sub>R)-mediated inhibition has a central role among the mechanisms underlying brain damage and the ensuing epilepsy and anxiety. During SE, calcium influx primarily via ionotropic glutamate receptors activates signaling cascades which trigger a rapid internalization of synaptic GABA<sub>A</sub>Rs; this weakens inhibition, exacerbating seizures and excitotoxicity. GABAergic interneurons are more susceptible to excitotoxic death than principal neurons. During the latent period of epileptogenesis, the aberrant reorganization in synaptic interactions that follow interneuronal loss in injured brain regions, leads to the formation of hyperexcitable, seizurogenic neuronal circuits, along with disturbances in brain oscillatory rhythms. Reduction in the spontaneous, rhythmic “bursts” of IPSCs in basolateral amygdala neurons is likely to play a central role in anxiogenesis. Protecting interneurons during SE is key to preventing both epilepsy and anxiety. Antiglutamatergic treatments, including antagonism of calcium-permeable AMPA receptors, can be expected to control seizures and reduce excitotoxicity not only by directly suppressing hyperexcitation, but also by counteracting the internalization of synaptic GABA<sub>A</sub>Rs. Benzodiazepines, as delayed treatment of SE, have low efficacy due to the reduction and dispersion of their targets (the synaptic GABA<sub>A</sub>Rs), but also because themselves contribute to further reduction of available GABA<sub>A</sub>Rs at the synapse; furthermore, benzodiazepines may be completely ineffective in the immature brain.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S096999612400233X/pdfft?md5=c552af560df42a7e28bede3ce7f9d51e&pid=1-s2.0-S096999612400233X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907173","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 : 2024-08-06DOI: 10.1016/j.nbd.2024.106632
Autoimmune encephalitis (AE) is an inflammatory disease of the central nervous system characterized by the production of various autoimmune antibodies targeting neuronal proteins. The pathogenesis of AE remains elusive. Accumulating evidence suggests that lymphocytes, particularly B and T lymphocytes, play an integral role in the development of AE. In the last two decades, autoimmune neural antibodies have taken center stage in diagnosing AE. Recently, increasing evidence has highlighted the importance of T lymphocytes in the onset of AE. CD4+ T cells are thought to influence disease progression by secreting associated cytokines, whereas CD8+ T cells exert a cytotoxic role, causing irreversible damage to neurons mainly in patients with paraneoplastic AE. Conventionally, the first-line treatments for AE include intravenous steroids, intravenous immunoglobulin, and plasma exchange to remove pathogenic autoantibodies. However, a minority of patients are insensitive to conventional first-line treatment protocols and suffer from disease relapse, a condition referred to as refractory AE. In recent years, new treatments, such as rituximab or CAAR-T, which target pathogenic lymphocytes in patients with AE, have offered new therapeutic options for refractory AE. This review aims to describe the current knowledge about the function of B and T lymphocytes in the pathophysiology of AE and to summarize and update the immunotherapy options for treating this disease.
自身免疫性脑炎(AE)是一种中枢神经系统炎症性疾病,其特征是产生针对神经元蛋白的各种自身免疫抗体。自身免疫性脑炎的发病机理仍然难以捉摸。越来越多的证据表明,淋巴细胞,尤其是 B 淋巴细胞和 T 淋巴细胞在 AE 的发病过程中起着不可或缺的作用。在过去二十年中,自身免疫性神经抗体已成为诊断 AE 的核心。最近,越来越多的证据强调了 T 淋巴细胞在 AE 发病中的重要性。CD4+ T 细胞被认为通过分泌相关细胞因子影响疾病进展,而 CD8+ T 细胞则发挥细胞毒性作用,主要对副肿瘤性 AE 患者的神经元造成不可逆转的损伤。传统上,AE 的一线治疗包括静脉注射类固醇、静脉注射免疫球蛋白和血浆置换以清除致病性自身抗体。然而,少数患者对传统的一线治疗方案不敏感,导致疾病复发,这种情况被称为难治性 AE。近年来,针对AE患者致病淋巴细胞的新疗法(如利妥昔单抗或CAAR-T)为难治性AE提供了新的治疗选择。本综述旨在描述目前有关 B 淋巴细胞和 T 淋巴细胞在 AE 病理生理学中的功能的知识,并总结和更新治疗这种疾病的免疫疗法方案。
{"title":"Lymphocytes in autoimmune encephalitis: Pathogenesis and therapeutic target","authors":"","doi":"10.1016/j.nbd.2024.106632","DOIUrl":"10.1016/j.nbd.2024.106632","url":null,"abstract":"<div><p>Autoimmune encephalitis (AE) is an inflammatory disease of the central nervous system characterized by the production of various autoimmune antibodies targeting neuronal proteins. The pathogenesis of AE remains elusive. Accumulating evidence suggests that lymphocytes, particularly B and T lymphocytes, play an integral role in the development of AE. In the last two decades, autoimmune neural antibodies have taken center stage in diagnosing AE. Recently, increasing evidence has highlighted the importance of T lymphocytes in the onset of AE. CD4<sup>+</sup> T cells are thought to influence disease progression by secreting associated cytokines, whereas CD8<sup>+</sup> T cells exert a cytotoxic role, causing irreversible damage to neurons mainly in patients with paraneoplastic AE. Conventionally, the first-line treatments for AE include intravenous steroids, intravenous immunoglobulin, and plasma exchange to remove pathogenic autoantibodies. However, a minority of patients are insensitive to conventional first-line treatment protocols and suffer from disease relapse, a condition referred to as refractory AE. In recent years, new treatments, such as rituximab or CAAR-T, which target pathogenic lymphocytes in patients with AE, have offered new therapeutic options for refractory AE. This review aims to describe the current knowledge about the function of B and T lymphocytes in the pathophysiology of AE and to summarize and update the immunotherapy options for treating this disease.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002328/pdfft?md5=cb16a141899e17a5588bc41b2d7a8f7c&pid=1-s2.0-S0969996124002328-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907175","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 : 2024-08-05DOI: 10.1016/j.nbd.2024.106627
An increasing number of people undergo anesthesia and surgery. Perioperative neurocognitive and depressive disorders are common central nervous system complications with similar pathogeneses. These conditions pose a deleterious threat to human health and a significant societal burden. In recent years, numerous studies have focused on the role of the gut microbiota and its metabolites in the central nervous system via the gut-brain axis. Its involvement in perioperative neurocognitive and depressive disorders has attracted considerable attention. This review aimed to elucidate the role of the gut microbiota and its metabolites in the pathogenesis of perioperative neurocognitive and depressive disorders, as well as the value of targeted interventions and treatments.
{"title":"Microbiota-gut-brain axis in perioperative neurocognitive and depressive disorders: Pathogenesis to treatment","authors":"","doi":"10.1016/j.nbd.2024.106627","DOIUrl":"10.1016/j.nbd.2024.106627","url":null,"abstract":"<div><p>An increasing number of people undergo anesthesia and surgery. Perioperative neurocognitive and depressive disorders are common central nervous system complications with similar pathogeneses. These conditions pose a deleterious threat to human health and a significant societal burden. In recent years, numerous studies have focused on the role of the gut microbiota and its metabolites in the central nervous system via the gut-brain axis. Its involvement in perioperative neurocognitive and depressive disorders has attracted considerable attention. This review aimed to elucidate the role of the gut microbiota and its metabolites in the pathogenesis of perioperative neurocognitive and depressive disorders, as well as the value of targeted interventions and treatments.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002274/pdfft?md5=37ca2e032fe500feda9e0d262e97b906&pid=1-s2.0-S0969996124002274-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902475","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 : 2024-08-05DOI: 10.1016/j.nbd.2024.106630
Despite growing descriptions of wild-type Huntingtin (wt-HTT) roles in both adult brain function and, more recently, development, several clinical trials are exploring HTT-lowering approaches that target both wt-HTT and the mutant isoform (mut-HTT) responsible for Huntington's disease (HD). This non-selective targeting is based on the autosomal dominant inheritance of HD, supporting the idea that mut-HTT exerts its harmful effects through a toxic gain-of-function or a dominant-negative mechanism. However, the precise amount of wt-HTT needed for healthy neurons in adults and during development remains unclear. In this study, we address this question by examining how wt-HTT loss affects human neuronal network formation, synaptic maturation, and homeostasis in vitro. Our findings establish a role of wt-HTT in the maturation of dendritic arborization and the acquisition of network-wide synchronized activity by human cortical neuronal networks modeled in vitro. Interestingly, the network synchronization defects only became apparent when more than two-thirds of the wt-HTT protein was depleted. Our study underscores the critical need to precisely understand wt-HTT role in neuronal health. It also emphasizes the potential risks of excessive wt-HTT loss associated with non-selective therapeutic approaches targeting both wt- and mut-HTT isoforms in HD patients.
{"title":"Huntingtin lowering impairs the maturation and synchronized synaptic activity of human cortical neuronal networks derived from induced pluripotent stem cells","authors":"","doi":"10.1016/j.nbd.2024.106630","DOIUrl":"10.1016/j.nbd.2024.106630","url":null,"abstract":"<div><p>Despite growing descriptions of wild-type Huntingtin (wt-HTT) roles in both adult brain function and, more recently, development, several clinical trials are exploring HTT-lowering approaches that target both wt-HTT and the mutant isoform (mut-HTT) responsible for Huntington's disease (HD). This non-selective targeting is based on the autosomal dominant inheritance of HD, supporting the idea that mut-HTT exerts its harmful effects through a toxic gain-of-function or a dominant-negative mechanism. However, the precise amount of wt-HTT needed for healthy neurons in adults and during development remains unclear. In this study, we address this question by examining how wt-HTT loss affects human neuronal network formation, synaptic maturation, and homeostasis in vitro. Our findings establish a role of wt-HTT in the maturation of dendritic arborization and the acquisition of network-wide synchronized activity by human cortical neuronal networks modeled in vitro. Interestingly, the network synchronization defects only became apparent when more than two-thirds of the wt-HTT protein was depleted. Our study underscores the critical need to precisely understand wt-HTT role in neuronal health. It also emphasizes the potential risks of excessive wt-HTT loss associated with non-selective therapeutic approaches targeting both wt- and mut-HTT isoforms in HD patients.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002304/pdfft?md5=7318bf2dee02efeee75f1f0d6a1f03fc&pid=1-s2.0-S0969996124002304-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897897","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 : 2024-08-05DOI: 10.1016/j.nbd.2024.106628
Autism Spectrum Disorders (ASD) encompass a wide array of debilitating symptoms, including severe sensory deficits and abnormal language development. Sensory deficits early in development may lead to broader symptomatology in adolescents and adults. The mechanistic links between ASD risk genes, sensory processing and language impairment are unclear. There is also a sex bias in ASD diagnosis and symptomatology. The current study aims to identify the developmental trajectory and genotype- and sex-dependent differences in auditory sensitivity and temporal processing in a Pten-deletion (phosphatase and tensin homolog missing on chromosome 10) mouse model of ASD. Auditory temporal processing is crucial for speech recognition and language development and deficits will cause language impairments. However, very little is known about the development of temporal processing in ASD animal models, and if there are sex differences. To address this major gap, we recorded epidural electroencephalography (EEG) signals from the frontal (FC) and auditory (AC) cortex in developing and adult Nse-cre PTEN mice, in which Pten is deleted in specific cortical layers (layers III-V) (PTEN conditional knock-out (cKO). We quantified resting EEG spectral power distribution, auditory event related potentials (ERP) and temporal processing from awake and freely moving male and female mice. Temporal processing is measured using a gap-in-noise-ASSR (auditory steady state response) stimulus paradigm. The experimental manipulation of gap duration and modulation depth allows us to measure cortical entrainment to rapid gaps in sounds. Temporal processing was quantified using inter-trial phase clustering (ITPC) values that account for phase consistency across trials. The results show genotype differences in resting power distribution in PTEN cKO mice throughout development. Male and female cKO mice have significantly increased beta power but decreased high frequency oscillations in the AC and FC. Both male and female PTEN cKO mice show diminished ITPC in their gap-ASSR responses in the AC and FC compared to control mice. Overall, deficits become more prominent in adult (p60) mice, with cKO mice having significantly increased sound evoked power and decreased ITPC compared to controls. While both male and female cKO mice demonstrated severe temporal processing deficits across development, female cKO mice showed increased hypersensitivity compared to males, reflected as increased N1 and P2 amplitudes. These data identify a number of novel sensory processing deficits in a PTEN-ASD mouse model that are present from an early age. Abnormal temporal processing and hypersensitive responses may contribute to abnormal development of language function in ASD.
{"title":"Developmental trajectory and sex differences in auditory processing in a PTEN-deletion model of autism spectrum disorders","authors":"","doi":"10.1016/j.nbd.2024.106628","DOIUrl":"10.1016/j.nbd.2024.106628","url":null,"abstract":"<div><p>Autism Spectrum Disorders (ASD) encompass a wide array of debilitating symptoms, including severe sensory deficits and abnormal language development. Sensory deficits early in development may lead to broader symptomatology in adolescents and adults. The mechanistic links between ASD risk genes, sensory processing and language impairment are unclear. There is also a sex bias in ASD diagnosis and symptomatology. The current study aims to identify the developmental trajectory and genotype- and sex-dependent differences in auditory sensitivity and temporal processing in a <em>Pten</em>-deletion (phosphatase and tensin homolog missing on chromosome 10) mouse model of ASD. Auditory temporal processing is crucial for speech recognition and language development and deficits will cause language impairments. However, very little is known about the development of temporal processing in ASD animal models, and if there are sex differences. To address this major gap, we recorded epidural electroencephalography (EEG) signals from the frontal (FC) and auditory (AC) cortex in developing and adult Nse-cre PTEN mice, in which <em>Pten</em> is deleted in specific cortical layers (layers III-V) (PTEN conditional knock-out (cKO). We quantified resting EEG spectral power distribution, auditory event related potentials (ERP) and temporal processing from awake and freely moving male and female mice. Temporal processing is measured using a gap-in-noise-ASSR (auditory steady state response) stimulus paradigm. The experimental manipulation of gap duration and modulation depth allows us to measure cortical entrainment to rapid gaps in sounds. Temporal processing was quantified using inter-trial phase clustering (ITPC) values that account for phase consistency across trials. The results show genotype differences in resting power distribution in PTEN cKO mice throughout development. Male and female cKO mice have significantly increased beta power but decreased high frequency oscillations in the AC and FC. Both male and female PTEN cKO mice show diminished ITPC in their gap-ASSR responses in the AC and FC compared to control mice. Overall, deficits become more prominent in adult (p60) mice, with cKO mice having significantly increased sound evoked power and decreased ITPC compared to controls. While both male and female cKO mice demonstrated severe temporal processing deficits across development, female cKO mice showed increased hypersensitivity compared to males, reflected as increased N1 and P2 amplitudes. These data identify a number of novel sensory processing deficits in a PTEN-ASD mouse model that are present from an early age. Abnormal temporal processing and hypersensitive responses may contribute to abnormal development of language function in ASD.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002286/pdfft?md5=10c9677e91d98e41040527fde1324b2a&pid=1-s2.0-S0969996124002286-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902473","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 : 2024-08-05DOI: 10.1016/j.nbd.2024.106631
Friedreich ataxia is a hereditary neurodegenerative disorder resulting from reduced levels of the protein frataxin due to an expanded GAA repeat in the FXN gene. This deficiency causes progressive degeneration of specific neuronal populations in the cerebellum and the consequent loss of movement coordination and equilibrium, which are some of the main symptoms observed in affected individuals. Like in other neurodegenerative diseases, previous studies suggest that glial cells could be involved in the neurodegenerative process and disease progression in patients with Friedreich ataxia.
In this work, we followed and characterized the progression of changes in the cerebellar cortex in the latest version of Friedreich ataxia humanized mouse model, YG8–800 (Fxnnull:YG8s(GAA)>800), which carries a human FXN transgene containing >800 GAA repeats.
Comparative analyses of behavioral, histopathological, and biochemical parameters were conducted between the control strain Y47R and YG8–800 mice at different time points. Our findings revealed that YG8–800 mice exhibit an ataxic phenotype characterized by poor motor coordination, decreased body weight, cerebellar atrophy, neuronal loss, and changes in synaptic proteins. Additionally, early activation of glial cells, predominantly astrocytes and microglia, was observed preceding neuronal degeneration, as was increased expression of key proinflammatory cytokines and downregulation of neurotrophic factors.
Together, our results show that the YG8–800 mouse model exhibits a stronger phenotype than previous experimental murine models, reliably recapitulating some of the features observed in humans. Accordingly, this humanized model could represent a valuable tool for studying Friedreich ataxia molecular disease mechanisms and for preclinical evaluation of possible therapies.
{"title":"Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8–800 murine model of Friedreich ataxia","authors":"","doi":"10.1016/j.nbd.2024.106631","DOIUrl":"10.1016/j.nbd.2024.106631","url":null,"abstract":"<div><p>Friedreich ataxia is a hereditary neurodegenerative disorder resulting from reduced levels of the protein frataxin due to an expanded GAA repeat in the <em>FXN</em> gene. This deficiency causes progressive degeneration of specific neuronal populations in the cerebellum and the consequent loss of movement coordination and equilibrium, which are some of the main symptoms observed in affected individuals. Like in other neurodegenerative diseases, previous studies suggest that glial cells could be involved in the neurodegenerative process and disease progression in patients with Friedreich ataxia.</p><p>In this work, we followed and characterized the progression of changes in the cerebellar cortex in the latest version of Friedreich ataxia humanized mouse model, YG8–800 (Fxn<sup>null</sup>:YG8s(GAA)<sub>>800</sub>), which carries a human <em>FXN</em> transgene containing >800 GAA repeats.</p><p>Comparative analyses of behavioral, histopathological, and biochemical parameters were conducted between the control strain Y47R and YG8–800 mice at different time points. Our findings revealed that YG8–800 mice exhibit an ataxic phenotype characterized by poor motor coordination, decreased body weight, cerebellar atrophy, neuronal loss, and changes in synaptic proteins. Additionally, early activation of glial cells, predominantly astrocytes and microglia, was observed preceding neuronal degeneration, as was increased expression of key proinflammatory cytokines and downregulation of neurotrophic factors.</p><p>Together, our results show that the YG8–800 mouse model exhibits a stronger phenotype than previous experimental murine models, reliably recapitulating some of the features observed in humans. Accordingly, this humanized model could represent a valuable tool for studying Friedreich ataxia molecular disease mechanisms and for preclinical evaluation of possible therapies.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002316/pdfft?md5=826328ae0cfb03c076f5f97707d517b9&pid=1-s2.0-S0969996124002316-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902474","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}