Pub Date : 2024-10-02DOI: 10.1016/j.nbd.2024.106689
Chunyan Cao, Vladimir Litvak, Shikun Zhan, Wei Liu, Chao Zhang, Bomin Sun, Dianyou Li, Bernadette C M van Wijk
Beta band oscillations in the sensorimotor cortex and subcortical structures, such as the subthalamic nucleus (STN) and internal pallidum (GPi), are closely linked to motor control. Recent research suggests that low-beta (14.5-23.5 Hz) and high-beta (23.5-35 Hz) cortico-STN coherence arise through distinct networks, possibly reflecting indirect and hyperdirect pathways. In this study, we sought to probe whether low- and high-beta coherence also exhibit different functional roles in facilitating and inhibiting movement. Twenty patients with Parkinson's disease who had deep brain stimulation electrodes implanted in either STN or GPi performed a classical go/nogo task while undergoing simultaneous magnetoencephalography and local field potentials recordings. Subjects' expectations were manipulated by presenting go- and nogo-trials with varying probabilities. We identified a lateral source in the sensorimotor cortex for low-beta coherence, as well as a medial source near the supplementary motor area for high-beta coherence. Task-related coherence time courses for these two sources revealed that low-beta coherence was more strongly implicated than high-beta coherence in the performance of go-trials. Accordingly, average pre-stimulus low-beta but not high-beta coherence or spectral power correlated with overall reaction time across subjects. High-beta coherence during unexpected nogo-trials was higher compared to expected nogo-trials at a relatively long latency of 3 s after stimulus presentation. Neither low- nor high-beta coherence showed a significant correlation with patients' symptom severity at baseline assessment. While low-beta cortico-subcortical coherence appears to be related to motor output, the role of high-beta coherence requires further investigation.
{"title":"Low-beta versus high-beta band cortico-subcortical coherence in movement inhibition and expectation.","authors":"Chunyan Cao, Vladimir Litvak, Shikun Zhan, Wei Liu, Chao Zhang, Bomin Sun, Dianyou Li, Bernadette C M van Wijk","doi":"10.1016/j.nbd.2024.106689","DOIUrl":"https://doi.org/10.1016/j.nbd.2024.106689","url":null,"abstract":"<p><p>Beta band oscillations in the sensorimotor cortex and subcortical structures, such as the subthalamic nucleus (STN) and internal pallidum (GPi), are closely linked to motor control. Recent research suggests that low-beta (14.5-23.5 Hz) and high-beta (23.5-35 Hz) cortico-STN coherence arise through distinct networks, possibly reflecting indirect and hyperdirect pathways. In this study, we sought to probe whether low- and high-beta coherence also exhibit different functional roles in facilitating and inhibiting movement. Twenty patients with Parkinson's disease who had deep brain stimulation electrodes implanted in either STN or GPi performed a classical go/nogo task while undergoing simultaneous magnetoencephalography and local field potentials recordings. Subjects' expectations were manipulated by presenting go- and nogo-trials with varying probabilities. We identified a lateral source in the sensorimotor cortex for low-beta coherence, as well as a medial source near the supplementary motor area for high-beta coherence. Task-related coherence time courses for these two sources revealed that low-beta coherence was more strongly implicated than high-beta coherence in the performance of go-trials. Accordingly, average pre-stimulus low-beta but not high-beta coherence or spectral power correlated with overall reaction time across subjects. High-beta coherence during unexpected nogo-trials was higher compared to expected nogo-trials at a relatively long latency of 3 s after stimulus presentation. Neither low- nor high-beta coherence showed a significant correlation with patients' symptom severity at baseline assessment. While low-beta cortico-subcortical coherence appears to be related to motor output, the role of high-beta coherence requires further investigation.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375711","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 : 2024-10-01DOI: 10.1016/j.nbd.2024.106687
Erika Velasquez, Ekaterina Savchenko, Sara Marmolejo-Martínez-Artesero, Désiré Challuau, Aline Aebi, Yuriy Pomeshchik, Nuno Jorge Lamas, Mauno Vihinen, Melinda Rezeli, Bernard Schneider, Cedric Raoul, Laurent Roybon
Astrocytes play a crucial role in the onset and progression of amyotrophic lateral sclerosis (ALS), a fatal disorder marked by the degeneration of motor neurons (MNs) in the central nervous system. Although astrocytes in ALS are known to be toxic to MNs, the pathological changes leading to their neurotoxic phenotype remain poorly understood. In this study, we generated human astrocytes from induced pluripotent stem cells (iPSCs) carrying the ALS-associated A4V mutation in superoxide dismutase 1 (SOD1) to examine early cellular pathways and network changes. Proteomic analysis revealed that ALS astrocytes are both dysfunctional and reactive compared to control astrocytes. We identified significant alterations in the levels of proteins linked to ALS pathology and the innate immune cGAS-STING pathway. Furthermore, we found that ALS astrocyte reactivity differs from that of control astrocytes treated with tumor necrosis factor alpha (TNFα), a key cytokine in inflammatory reactions. We then evaluated the potential of fibroblast growth factor (FGF) 2, 4, 16, and 18 to reverse ALS astrocyte phenotype. Among these, FGF4 successfully reversed ALS astrocyte dysfunction and reactivity in vitro. When delivered to the spinal cord of the SOD1G93A mouse model of ALS, FGF4 lowered astrocyte reactivity. However, this was not sufficient to protect MNs from cell death. Further analysis indicated that TNFα abrogated the reactivity reduction achieved by FGF4, suggesting that complete rescue of the ALS phenotype by FGF4 is hindered by ongoing complex neuroinflammatory processes in vivo. In summary, our data demonstrate that astrocytes generated from ALS iPSCs are inherently dysfunctional and exhibit an immune reactive phenotype. Effectively targeting astrocyte dysfunction and reactivity in vivo may help mitigate ALS and prevent MN death.
星形胶质细胞在肌萎缩性脊髓侧索硬化症(ALS)的发病和发展过程中起着至关重要的作用,这是一种以中枢神经系统运动神经元(MNs)变性为特征的致命性疾病。虽然已知 ALS 中的星形胶质细胞对 MNs 有毒性,但导致其神经毒性表型的病理变化仍鲜为人知。在这项研究中,我们从携带 ALS 相关超氧化物歧化酶 1(SOD1)A4V 突变的诱导多能干细胞(iPSCs)中生成了人类星形胶质细胞,以研究早期的细胞通路和网络变化。蛋白质组分析表明,与对照组星形胶质细胞相比,ALS 星形胶质细胞既有功能障碍,又有反应性。我们发现与 ALS 病理学和先天性免疫 cGAS-STING 通路相关的蛋白质水平发生了重大变化。此外,我们还发现 ALS 星形胶质细胞的反应性不同于用肿瘤坏死因子α(TNFα)处理的对照组星形胶质细胞,肿瘤坏死因子α是炎症反应中的一种关键细胞因子。我们随后评估了成纤维细胞生长因子(FGF)2、4、16 和 18 逆转 ALS 星形胶质细胞表型的潜力。其中,FGF4 在体外成功逆转了 ALS 星形胶质细胞的功能障碍和反应性。当将 FGF4 运送到 SOD1G93A ALS 小鼠模型的脊髓中时,它能降低星形胶质细胞的反应性。然而,这并不足以保护 MN 免于细胞死亡。进一步的分析表明,TNFα 会削弱 FGF4 所实现的反应性降低,这表明 FGF4 对 ALS 表型的完全拯救受到了体内正在进行的复杂神经炎症过程的阻碍。总之,我们的数据证明,由 ALS iPSCs 生成的星形胶质细胞本身存在功能障碍,并表现出免疫反应表型。在体内有效靶向星形胶质细胞的功能障碍和反应性可能有助于缓解 ALS 并防止 MN 死亡。
{"title":"TNFα prevents FGF4-mediated rescue of astrocyte dysfunction and reactivity in human ALS models.","authors":"Erika Velasquez, Ekaterina Savchenko, Sara Marmolejo-Martínez-Artesero, Désiré Challuau, Aline Aebi, Yuriy Pomeshchik, Nuno Jorge Lamas, Mauno Vihinen, Melinda Rezeli, Bernard Schneider, Cedric Raoul, Laurent Roybon","doi":"10.1016/j.nbd.2024.106687","DOIUrl":"https://doi.org/10.1016/j.nbd.2024.106687","url":null,"abstract":"<p><p>Astrocytes play a crucial role in the onset and progression of amyotrophic lateral sclerosis (ALS), a fatal disorder marked by the degeneration of motor neurons (MNs) in the central nervous system. Although astrocytes in ALS are known to be toxic to MNs, the pathological changes leading to their neurotoxic phenotype remain poorly understood. In this study, we generated human astrocytes from induced pluripotent stem cells (iPSCs) carrying the ALS-associated A4V mutation in superoxide dismutase 1 (SOD1) to examine early cellular pathways and network changes. Proteomic analysis revealed that ALS astrocytes are both dysfunctional and reactive compared to control astrocytes. We identified significant alterations in the levels of proteins linked to ALS pathology and the innate immune cGAS-STING pathway. Furthermore, we found that ALS astrocyte reactivity differs from that of control astrocytes treated with tumor necrosis factor alpha (TNFα), a key cytokine in inflammatory reactions. We then evaluated the potential of fibroblast growth factor (FGF) 2, 4, 16, and 18 to reverse ALS astrocyte phenotype. Among these, FGF4 successfully reversed ALS astrocyte dysfunction and reactivity in vitro. When delivered to the spinal cord of the SOD1<sup>G93A</sup> mouse model of ALS, FGF4 lowered astrocyte reactivity. However, this was not sufficient to protect MNs from cell death. Further analysis indicated that TNFα abrogated the reactivity reduction achieved by FGF4, suggesting that complete rescue of the ALS phenotype by FGF4 is hindered by ongoing complex neuroinflammatory processes in vivo. In summary, our data demonstrate that astrocytes generated from ALS iPSCs are inherently dysfunctional and exhibit an immune reactive phenotype. Effectively targeting astrocyte dysfunction and reactivity in vivo may help mitigate ALS and prevent MN death.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372375","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}
Corticobasal degeneration (CBD) is a major four-repeat tauopathy along with progressive supranuclear palsy (PSP). Although detergent-insoluble 37-40-kDa carboxyl-terminal tau fragments (CTFs) are hallmarks of CBD pathology, the process of their formation is unknown. This study monitored the formation of CBD-type fibrils that exhibit astrocytic plaques, a characteristic CBD pathology, using its biochemical properties different from those of Alzheimer's disease/PSP-type fibrils. Tau fibrils from patients with CBD were amplified in non-astrocytic cultured cells, which maintained CBD-specific biochemical properties. We found that the lysosomal protease Legumain (LGMN) was involved in the generation of CBD-specific 37-40-kDa CTFs. While LGMN cleaved tau fibrils at Asn167 and Asn368 in the brain tissues of patients with Alzheimer's disease and PSP, tau fibrils from patients with CBD were predominantly resistant to cleavage at Asn368 by LGMN, resulting in the generation of CBD-specific CTFs. LGMN preference in tau fibrils was lost upon unraveling the tau fibril fold, suggesting that the CBD-specific tau fibril fold contributes to CBD-specific CTF production. From these findings, we found a way to differentiate astrocytic plaque from tufted astrocyte using the anti-Asn368 LGMN cleavage site-specific antibody. Inoculation of tau fibrils amplified in non-astrocytic cells into the mouse brain reproduced LGMN-resistant tau fibrils and recapitulated anti-Asn368-negative astrocytic plaques, which are characteristic of CBD pathology. This study supports the existence of disease-specific tau fibrils and contribute to further understanding of the tauopathy diagnosis. Our tau propagation mouse model using cellular tau seeds may contribute to uncovering disease mechanisms and screening for potential therapeutic compounds.
皮质基底层变性(CBD)与进行性核上性麻痹(PSP)一样,是一种主要的四重复tau病。虽然去污剂不溶性的37-40-kDa羧基末端tau片段(CTFs)是CBD病理学的标志,但其形成过程尚不清楚。本研究利用CBD型纤维与阿尔茨海默病/PSP型纤维不同的生化特性,监测了CBD型纤维的形成过程,CBD病理特征之一是星形胶质斑块。来自 CBD 患者的 Tau 纤维在非星形细胞培养细胞中得到扩增,并保持了 CBD 特有的生化特性。我们发现溶酶体蛋白酶Legumain(LGMN)参与了CBD特异性37-40-kDa CTFs的生成。在阿尔茨海默氏症和帕金森氏症患者的脑组织中,LGMN能在Asn167和Asn368处裂解tau纤维,而CBD患者的tau纤维则主要对LGMN在Asn368处的裂解具有抵抗力,从而产生了CBD特异性CTFs。在解开tau纤维折叠后,LGMN对tau纤维的偏好就消失了,这表明CBD特异性tau纤维折叠有助于CBD特异性CTF的产生。根据这些发现,我们找到了一种利用抗Asn368 LGMN裂解位点特异性抗体区分星形胶质细胞斑块和丛星形胶质细胞的方法。将在非星形胶质细胞中扩增的 tau 纤维接种到小鼠大脑中,可再现抗 LGMN 的 tau 纤维,并再现抗Asn368 阴性的星形胶质细胞斑块,这是 CBD 病理学的特征。这项研究证实了疾病特异性tau纤维的存在,有助于进一步了解tau病的诊断。我们利用细胞tau种子建立的tau传播小鼠模型可能有助于揭示疾病机制和筛选潜在的治疗化合物。
{"title":"Legumain/asparaginyl endopeptidase-resistant tau fibril fold produces corticobasal degeneration-specific C-terminal tau fragment.","authors":"Daisuke Taniguchi, Shotaro Shimonaka, Ahmed Imtiaz, Montasir Elahi, Taku Hatano, Yuzuru Imai, Nobutaka Hattori","doi":"10.1016/j.nbd.2024.106686","DOIUrl":"https://doi.org/10.1016/j.nbd.2024.106686","url":null,"abstract":"<p><p>Corticobasal degeneration (CBD) is a major four-repeat tauopathy along with progressive supranuclear palsy (PSP). Although detergent-insoluble 37-40-kDa carboxyl-terminal tau fragments (CTFs) are hallmarks of CBD pathology, the process of their formation is unknown. This study monitored the formation of CBD-type fibrils that exhibit astrocytic plaques, a characteristic CBD pathology, using its biochemical properties different from those of Alzheimer's disease/PSP-type fibrils. Tau fibrils from patients with CBD were amplified in non-astrocytic cultured cells, which maintained CBD-specific biochemical properties. We found that the lysosomal protease Legumain (LGMN) was involved in the generation of CBD-specific 37-40-kDa CTFs. While LGMN cleaved tau fibrils at Asn167 and Asn368 in the brain tissues of patients with Alzheimer's disease and PSP, tau fibrils from patients with CBD were predominantly resistant to cleavage at Asn368 by LGMN, resulting in the generation of CBD-specific CTFs. LGMN preference in tau fibrils was lost upon unraveling the tau fibril fold, suggesting that the CBD-specific tau fibril fold contributes to CBD-specific CTF production. From these findings, we found a way to differentiate astrocytic plaque from tufted astrocyte using the anti-Asn368 LGMN cleavage site-specific antibody. Inoculation of tau fibrils amplified in non-astrocytic cells into the mouse brain reproduced LGMN-resistant tau fibrils and recapitulated anti-Asn368-negative astrocytic plaques, which are characteristic of CBD pathology. This study supports the existence of disease-specific tau fibrils and contribute to further understanding of the tauopathy diagnosis. Our tau propagation mouse model using cellular tau seeds may contribute to uncovering disease mechanisms and screening for potential therapeutic compounds.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365889","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 : 2024-09-27DOI: 10.1016/j.nbd.2024.106685
Mariangela Scarduzio, Karen L Eskow Jaunarajs, David G Standaert
Altered interaction between striatonigral dopaminergic (DA) inputs and local acetylcholine (ACh) in striatum has long been hypothesized to play a central role in the pathophysiology of dystonia and dyskinesia. Indeed, previous research using several genetic mouse models of human isolated dystonia identified a shared endophenotype with paradoxical excitation of striatal cholinergic interneuron (ChIs) activity in response to activation of dopamine D2 receptors (D2R). These mouse models lack a dystonic motor phenotype, which leaves a critical gap in comprehending the role of DA and ACh transmission in the manifestations of dystonia. To tackle this question, we used a combination of ex vivo slice physiology and in vivo monitoring of striatal ACh dynamics in the inducible, phenotypically penetrant, transgenic mouse model of paroxysmal non-kinesiogenic dyskinesia (PNKD), an animal with both dystonic and dyskinetic features. We found that, similarly to genetic models of isolated dystonia, the PNKD mouse displays D2R-induced paradoxical excitation of ChI firing in ex vivo striatal brain slices. In vivo, caffeine triggers dystonic symptoms while reversing the D2R-mediated excitation of ChIs and desynchronizing ACh release in PNKD mice. In WT littermate controls, caffeine stimulates spontaneous locomotion through a similar but reversed mechanism involving an excitatory switch of the D2R control of ChI activity, associated with enhanced synchronization of ACh release. These observations suggest that the "paradoxical excitation" of cholinergic interneurons described in isolated dystonia models could represent a compensatory or protective mechanism that prevents manifestation of movement abnormalities and that phenotypic dystonia is possible only when this is absent. These findings also suggest that D2Rs may play an important role in synchronizing the ChI network leading to rhythmic ACh release during heightened movement states. Dysfunction of this interaction and corresponding desynchrony of ACh release may contribute to aberrant movements.
长期以来,人们一直假设纹状体多巴胺能(DA)输入与纹状体局部乙酰胆碱(ACh)之间的相互作用发生了改变,从而在肌张力障碍和运动障碍的病理生理学中扮演了核心角色。事实上,先前利用几种人类孤立性肌张力障碍遗传小鼠模型进行的研究发现了一种共同的内表型,即纹状体胆碱能中间神经元(ChIs)活动对多巴胺 D2 受体(D2R)激活的反常兴奋反应。这些小鼠模型缺乏肌张力障碍运动表型,因此在理解 DA 和 ACh 传导在肌张力障碍表现中的作用方面留下了关键的空白。为了解决这个问题,我们在具有肌张力障碍和运动障碍特征的诱导型、表型穿透性转基因小鼠阵发性非肌动源性运动障碍(PNKD)模型中结合使用了体外切片生理学和体内纹状体 ACh 动态监测。我们发现,与孤立性肌张力障碍的遗传模型类似,PNKD 小鼠在体外纹状体脑切片中也表现出 D2R 诱导的 ChI 发火悖论性兴奋。在体内,咖啡因会引发肌张力障碍症状,同时逆转 D2R 介导的 ChIs 兴奋,并使 PNKD 小鼠的 ACh 释放不同步。在 WT 小鼠对照组中,咖啡因通过一种类似但逆转的机制刺激小鼠自发运动,这种机制涉及 D2R 控制 ChI 活动的兴奋转换,并与 ACh 释放的同步化增强有关。这些观察结果表明,在离体肌张力障碍模型中描述的胆碱能中间神经元的 "矛盾性兴奋 "可能代表了一种防止运动异常表现的代偿或保护机制,只有当这种机制缺失时,才可能出现表型肌张力障碍。这些研究结果还表明,D2Rs 可能在同步化 ChI 网络中发挥重要作用,从而导致在运动增强状态下有节律地释放 ACh。这种相互作用的功能障碍和相应的 ACh 释放不同步可能会导致异常运动。
{"title":"Striatal cholinergic transmission in an inducible transgenic mouse model of paroxysmal non-kinesiogenic dyskinesia.","authors":"Mariangela Scarduzio, Karen L Eskow Jaunarajs, David G Standaert","doi":"10.1016/j.nbd.2024.106685","DOIUrl":"https://doi.org/10.1016/j.nbd.2024.106685","url":null,"abstract":"<p><p>Altered interaction between striatonigral dopaminergic (DA) inputs and local acetylcholine (ACh) in striatum has long been hypothesized to play a central role in the pathophysiology of dystonia and dyskinesia. Indeed, previous research using several genetic mouse models of human isolated dystonia identified a shared endophenotype with paradoxical excitation of striatal cholinergic interneuron (ChIs) activity in response to activation of dopamine D2 receptors (D2R). These mouse models lack a dystonic motor phenotype, which leaves a critical gap in comprehending the role of DA and ACh transmission in the manifestations of dystonia. To tackle this question, we used a combination of ex vivo slice physiology and in vivo monitoring of striatal ACh dynamics in the inducible, phenotypically penetrant, transgenic mouse model of paroxysmal non-kinesiogenic dyskinesia (PNKD), an animal with both dystonic and dyskinetic features. We found that, similarly to genetic models of isolated dystonia, the PNKD mouse displays D2R-induced paradoxical excitation of ChI firing in ex vivo striatal brain slices. In vivo, caffeine triggers dystonic symptoms while reversing the D2R-mediated excitation of ChIs and desynchronizing ACh release in PNKD mice. In WT littermate controls, caffeine stimulates spontaneous locomotion through a similar but reversed mechanism involving an excitatory switch of the D2R control of ChI activity, associated with enhanced synchronization of ACh release. These observations suggest that the \"paradoxical excitation\" of cholinergic interneurons described in isolated dystonia models could represent a compensatory or protective mechanism that prevents manifestation of movement abnormalities and that phenotypic dystonia is possible only when this is absent. These findings also suggest that D2Rs may play an important role in synchronizing the ChI network leading to rhythmic ACh release during heightened movement states. Dysfunction of this interaction and corresponding desynchrony of ACh release may contribute to aberrant movements.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350673","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}
Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor deficits due to the depletion of nigrostriatal dopamine. Stem cell differentiation therapy emerges as a promising treatment option for sustained symptom relief. In this study, we successfully developed a one-step differentiation system using the YFBP cocktail (Y27632, Forskolin, SB431542, and SP600125) to effectively convert human umbilical cord mesenchymal stem cells (hUCMSCs) into dopaminergic neurons without genetic modification. This approach addresses the challenge of rapidly and safely generating functional neurons on a large scale. After a 7-day induction period, over 80 % of the cells were double-positive for TUBB3 and NEUN. Transcriptome analysis revealed the dual roles of the cocktail in inducing fate erasure in mesenchymal stem cells and activating the neuronal program. Notably, these chemically induced cells (CiNs) did not express HLA class II genes, preserving their immune-privileged status. Further study indicated that YFBP significantly downregulated p53 signaling and accelerated the differentiation process when Pifithrin-α, a p53 signaling inhibitor, was applied. Additionally, Wnt/β-catenin signaling was transiently activated within one day, but the prolonged activation hindered the neuronal differentiation of hUCMSCs. Upon transplantation into the striatum of mice, CiNs survived well and tested positive for dopaminergic neuron markers. They exhibited typical action potentials and sodium and potassium ion channel activity, demonstrating neuronal electrophysiological activity. Furthermore, CiNs treatment significantly increased the number of tyrosine hydroxylase-positive cells and the concentration of dopamine in the striatum, effectively ameliorating movement disorders in PD mice. Overall, our study provides a secure and reliable framework for cell replacement therapy for Parkinson's disease.
{"title":"Direct conversion of human umbilical cord mesenchymal stem cells into dopaminergic neurons for Parkinson's disease treatment.","authors":"Jinming Liu, Zhongqing Ji, Qisheng He, Huanhuan Chen, Xiaojing Xu, Qiuhao Mei, Ya'nan Hu, Huanxiang Zhang","doi":"10.1016/j.nbd.2024.106683","DOIUrl":"10.1016/j.nbd.2024.106683","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor deficits due to the depletion of nigrostriatal dopamine. Stem cell differentiation therapy emerges as a promising treatment option for sustained symptom relief. In this study, we successfully developed a one-step differentiation system using the YFBP cocktail (Y27632, Forskolin, SB431542, and SP600125) to effectively convert human umbilical cord mesenchymal stem cells (hUCMSCs) into dopaminergic neurons without genetic modification. This approach addresses the challenge of rapidly and safely generating functional neurons on a large scale. After a 7-day induction period, over 80 % of the cells were double-positive for TUBB3 and NEUN. Transcriptome analysis revealed the dual roles of the cocktail in inducing fate erasure in mesenchymal stem cells and activating the neuronal program. Notably, these chemically induced cells (CiNs) did not express HLA class II genes, preserving their immune-privileged status. Further study indicated that YFBP significantly downregulated p53 signaling and accelerated the differentiation process when Pifithrin-α, a p53 signaling inhibitor, was applied. Additionally, Wnt/β-catenin signaling was transiently activated within one day, but the prolonged activation hindered the neuronal differentiation of hUCMSCs. Upon transplantation into the striatum of mice, CiNs survived well and tested positive for dopaminergic neuron markers. They exhibited typical action potentials and sodium and potassium ion channel activity, demonstrating neuronal electrophysiological activity. Furthermore, CiNs treatment significantly increased the number of tyrosine hydroxylase-positive cells and the concentration of dopamine in the striatum, effectively ameliorating movement disorders in PD mice. Overall, our study provides a secure and reliable framework for cell replacement therapy for Parkinson's disease.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350770","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 : 2024-09-26DOI: 10.1016/j.nbd.2024.106684
Siqi Gong, Xiuying Cai, Yue Wang, Jiaxing Wang, Haixing Xiao, Lei Bai, Juehua Zhu, Xiang Li
Vascular cognitive impairment (VCI) is a clinical syndrome that arises from cerebrovascular issues and associated risk factors, resulting in difficulties in at least one area of cognitive function. VCI has emerged as the second most prevalent type of dementia following Alzheimer's disease, yet there is no effective clinical treatment. Botch, an endogenous Notch1 antagonist, demonstrates neuroprotective effects by inhibiting neuroinflammatory responses mediated through the Notch pathway. While its role in stroke-induced neuroinflammation is well-established, its involvement in VCI remains largely unexplored. This study investigates the role and potential mechanisms of Botch in a rat model of cognitive impairment caused by bilateral common carotid artery occlusion (BCCAO). Firstly, we observed that Botch levels were down-regulated in BCCAO rats, which correlated with increased release of inflammatory cytokines and neuronal damage. Microglia in BCCAO rats released interleukin-1α (IL-1α), tumor necrosis factor-α (TNF-α), and complement component 1q (C1q), leading to the activation of neurotoxic C3+ A1 reactive astrocytes. Then, the down-regulation of Botch exacerbated microglia-mediated inflammation, activated C3+ A1 astrocytes, worsened neuronal damage, and led to a decline in cognitive function. Conversely, the re-expression of Botch alleviated C3+ astrocyte activation, inhibited neuronal damage, and improved mental function. In conclusion, Botch plays a crucial role in inhibiting neuroinflammation induced by type A1 reactive astrocytes. It achieves this by blocking the activation of microglia triggered by the Notch pathway. Ultimately, it inhibits neuronal damage to play a neuroprotective role. These findings suggest that Botch may represent a novel potential target for treating VCI.
{"title":"Botch improves cognitive impairment after cerebral ischemia associated with microglia-induced A1-type astrocyte activation.","authors":"Siqi Gong, Xiuying Cai, Yue Wang, Jiaxing Wang, Haixing Xiao, Lei Bai, Juehua Zhu, Xiang Li","doi":"10.1016/j.nbd.2024.106684","DOIUrl":"10.1016/j.nbd.2024.106684","url":null,"abstract":"<p><p>Vascular cognitive impairment (VCI) is a clinical syndrome that arises from cerebrovascular issues and associated risk factors, resulting in difficulties in at least one area of cognitive function. VCI has emerged as the second most prevalent type of dementia following Alzheimer's disease, yet there is no effective clinical treatment. Botch, an endogenous Notch1 antagonist, demonstrates neuroprotective effects by inhibiting neuroinflammatory responses mediated through the Notch pathway. While its role in stroke-induced neuroinflammation is well-established, its involvement in VCI remains largely unexplored. This study investigates the role and potential mechanisms of Botch in a rat model of cognitive impairment caused by bilateral common carotid artery occlusion (BCCAO). Firstly, we observed that Botch levels were down-regulated in BCCAO rats, which correlated with increased release of inflammatory cytokines and neuronal damage. Microglia in BCCAO rats released interleukin-1α (IL-1α), tumor necrosis factor-α (TNF-α), and complement component 1q (C1q), leading to the activation of neurotoxic C3+ A1 reactive astrocytes. Then, the down-regulation of Botch exacerbated microglia-mediated inflammation, activated C3+ A1 astrocytes, worsened neuronal damage, and led to a decline in cognitive function. Conversely, the re-expression of Botch alleviated C3+ astrocyte activation, inhibited neuronal damage, and improved mental function. In conclusion, Botch plays a crucial role in inhibiting neuroinflammation induced by type A1 reactive astrocytes. It achieves this by blocking the activation of microglia triggered by the Notch pathway. Ultimately, it inhibits neuronal damage to play a neuroprotective role. These findings suggest that Botch may represent a novel potential target for treating VCI.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350769","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.nbd.2024.106682
Ayan Mohamud Yusuf, Xiaoni Zhang, Erich Gulbins, Ying Peng, Nina Hagemann, Dirk M Hermann
Sphingolipids comprise a class of lipids, which are composed of a sphingoid base backbone and are essential structural components of cell membranes. Beyond their role in maintaining cellular integrity, several sphingolipids are pivotally involved in signaling pathways controlling cell proliferation, differentiation, and death. The brain exhibits a particularly high concentration of sphingolipids and dysregulation of the sphingolipid metabolism due to ischemic injury is implicated in consecutive pathological events. Experimental stroke studies revealed that the stress sphingolipid ceramide accumulates in the ischemic brain post-stroke. Specifically, counteracting ceramide accumulation protects against ischemic damage and promotes brain remodeling, which translates into improved behavioral outcome. Sphingomyelin substantially influences cell membrane fluidity and thereby controls the release of extracellular vesicles, which are important vehicles in cellular communication. By modulating sphingomyelin content, these vesicles were shown to contribute to behavioral recovery in experimental stroke studies. Another important sphingolipid that influences stroke pathology is sphingosine-1-phosphate, which has been attributed a pro-angiogenic function, that is presumably mediated by its effect on endothelial function and/or immune cell trafficking. In experimental and clinical studies, sphingosine-1-phosphate receptor modulators allowed to modify clinically significant stroke recovery. Due to their pivotal roles in cell signaling, pharmacological compounds modulating sphingolipids, their enzymes or receptors hold promise as therapeutics in human stroke patients.
{"title":"Signaling roles of sphingolipids in the ischemic brain and their potential utility as therapeutic targets.","authors":"Ayan Mohamud Yusuf, Xiaoni Zhang, Erich Gulbins, Ying Peng, Nina Hagemann, Dirk M Hermann","doi":"10.1016/j.nbd.2024.106682","DOIUrl":"10.1016/j.nbd.2024.106682","url":null,"abstract":"<p><p>Sphingolipids comprise a class of lipids, which are composed of a sphingoid base backbone and are essential structural components of cell membranes. Beyond their role in maintaining cellular integrity, several sphingolipids are pivotally involved in signaling pathways controlling cell proliferation, differentiation, and death. The brain exhibits a particularly high concentration of sphingolipids and dysregulation of the sphingolipid metabolism due to ischemic injury is implicated in consecutive pathological events. Experimental stroke studies revealed that the stress sphingolipid ceramide accumulates in the ischemic brain post-stroke. Specifically, counteracting ceramide accumulation protects against ischemic damage and promotes brain remodeling, which translates into improved behavioral outcome. Sphingomyelin substantially influences cell membrane fluidity and thereby controls the release of extracellular vesicles, which are important vehicles in cellular communication. By modulating sphingomyelin content, these vesicles were shown to contribute to behavioral recovery in experimental stroke studies. Another important sphingolipid that influences stroke pathology is sphingosine-1-phosphate, which has been attributed a pro-angiogenic function, that is presumably mediated by its effect on endothelial function and/or immune cell trafficking. In experimental and clinical studies, sphingosine-1-phosphate receptor modulators allowed to modify clinically significant stroke recovery. Due to their pivotal roles in cell signaling, pharmacological compounds modulating sphingolipids, their enzymes or receptors hold promise as therapeutics in human stroke patients.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350672","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.nbd.2024.106681
Lenadogene nolparvovec is a gene therapy which has been developed to treat Leber hereditary optic neuropathy (LHON) caused by a point mutation in the mitochondrial NADH dehydrogenase 4 (ND4) gene. Clinical trials have demonstrated a significant improvement of visual acuity up to 5 years after treatment by lenadogene nolparvovec but, surprisingly, unilateral treatment resulted in bilateral improvement of vision. This contralateral effect – similarly observed with other gene therapy products in development for MT-ND4-LHON – is supported by the migration of viral vector genomes and their transcripts to the contralateral eye, as reported in animals, and post-mortem samples from two patients. In this study, we used an AAV2 encoding fluorescent proteins targeting mitochondria to investigate whether these organelles themselves could transfer from the treated eye to the fellow one. We found that mitochondria travel along the visual system (optic chiasm and primary visual cortex) and reach the contralateral eye (optic nerve and retina) in physiological conditions. We also observed that, in a rotenone-induced model of retinal damage mimicking LHON, mitochondrial transfer from the healthy to the damaged eye was accelerated and enhanced. Our results thus provide a further explanation for the contralateral beneficial effect observed during clinical studies with lenadogene nolparvovec.
{"title":"Retinal damage promotes mitochondrial transfer in the visual system of a mouse model of Leber hereditary optic neuropathy","authors":"","doi":"10.1016/j.nbd.2024.106681","DOIUrl":"10.1016/j.nbd.2024.106681","url":null,"abstract":"<div><div>Lenadogene nolparvovec is a gene therapy which has been developed to treat Leber hereditary optic neuropathy (LHON) caused by a point mutation in the mitochondrial NADH dehydrogenase 4 (<em>ND4</em>) gene. Clinical trials have demonstrated a significant improvement of visual acuity up to 5 years after treatment by lenadogene nolparvovec but, surprisingly, unilateral treatment resulted in bilateral improvement of vision. This contralateral effect – similarly observed with other gene therapy products in development for <em>MT-ND4</em>-LHON – is supported by the migration of viral vector genomes and their transcripts to the contralateral eye, as reported in animals, and post-mortem samples from two patients. In this study, we used an AAV2 encoding fluorescent proteins targeting mitochondria to investigate whether these organelles themselves could transfer from the treated eye to the fellow one. We found that mitochondria travel along the visual system (optic chiasm and primary visual cortex) and reach the contralateral eye (optic nerve and retina) in physiological conditions. We also observed that, in a rotenone-induced model of retinal damage mimicking LHON, mitochondrial transfer from the healthy to the damaged eye was accelerated and enhanced. Our results thus provide a further explanation for the contralateral beneficial effect observed during clinical studies with lenadogene nolparvovec.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350771","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 : 2024-09-24DOI: 10.1016/j.nbd.2024.106680
Despite effective antiretroviral therapy, cognitive impairment remains prevalent among people with HIV (PWH) and decrements in executive function are particularly prominent. One component of executive function is cognitive flexibility, which integrates a variety of executive functions to dynamically adapt one's behavior in response to changing contextual demands. Though substantial work has illuminated HIV-related aberrations in brain function, it remains unclear how the neural oscillatory dynamics serving cognitive flexibility are affected by HIV-related alterations in neural functioning. Herein, 149 participants (PWH: 74; seronegative controls: 75) between the ages of 29–76 years completed a perceptual feature matching task that probes cognitive flexibility during high-density magnetoencephalography (MEG). Neural responses were decomposed into the time-frequency domain and significant oscillatory responses in the theta (4–8 Hz), alpha (10–16 Hz), and gamma (74–98 Hz) spectral windows were imaged using a beamforming approach. Whole-brain voxel-wise comparisons were then conducted on these dynamic functional maps to identify HIV-related differences in the neural oscillatory dynamics supporting cognitive flexibility. Our findings indicated group differences in alpha oscillatory activity in the cingulo-opercular cortices, and differences in gamma activity were found in the cerebellum. Across all participants, alpha and gamma activity in these regions were associated with performance on the cognitive flexibility task. Further, PWH who had been treated with antiretroviral therapy for a longer duration and those with higher current CD4 counts had alpha responses that more closely resembled those of seronegative controls, suggesting that optimal clinical management of HIV infection is associated with preserved neural dynamics supporting cognitive flexibility.
尽管抗逆转录病毒疗法很有效,但在艾滋病病毒感染者(PWH)中,认知障碍仍然很普遍,而执行功能的下降尤为突出。执行功能的一个组成部分是认知灵活性,它整合了各种执行功能,以动态调整自己的行为,应对不断变化的环境需求。尽管已有大量研究揭示了与艾滋病病毒相关的大脑功能异常,但认知灵活性的神经振荡动态如何受到与艾滋病病毒相关的神经功能改变的影响仍不清楚。在本文中,149 名年龄在 29-76 岁之间的参与者(艾滋病感染者:74 人;血清阴性对照组:75 人)完成了一项感知特征匹配任务,该任务通过高密度脑磁图(MEG)探测认知灵活性。神经反应被分解到时频域,并使用波束成形方法对θ(4-8赫兹)、α(10-16赫兹)和γ(74-98赫兹)频谱窗口中的显著振荡反应进行成像。然后对这些动态功能图进行全脑体素比较,以确定支持认知灵活性的神经振荡动态中与 HIV 相关的差异。我们的研究结果表明,杏仁核-小脑皮层的阿尔法振荡活动存在群体差异,小脑的伽马活动也存在差异。在所有参与者中,这些区域的α和γ活动与认知灵活性任务的表现有关。此外,接受抗逆转录病毒治疗时间较长的艾滋病感染者和目前 CD4 细胞数较高的艾滋病感染者的阿尔法反应与血清阴性对照组的反应更为相似,这表明艾滋病感染的最佳临床治疗与支持认知灵活性的神经动态的保留有关。
{"title":"People with HIV exhibit spectrally distinct patterns of rhythmic cortical activity serving cognitive flexibility","authors":"","doi":"10.1016/j.nbd.2024.106680","DOIUrl":"10.1016/j.nbd.2024.106680","url":null,"abstract":"<div><div>Despite effective antiretroviral therapy, cognitive impairment remains prevalent among people with HIV (PWH) and decrements in executive function are particularly prominent. One component of executive function is cognitive flexibility, which integrates a variety of executive functions to dynamically adapt one's behavior in response to changing contextual demands. Though substantial work has illuminated HIV-related aberrations in brain function, it remains unclear how the neural oscillatory dynamics serving cognitive flexibility are affected by HIV-related alterations in neural functioning. Herein, 149 participants (PWH: 74; seronegative controls: 75) between the ages of 29–76 years completed a perceptual feature matching task that probes cognitive flexibility during high-density magnetoencephalography (MEG). Neural responses were decomposed into the time-frequency domain and significant oscillatory responses in the theta (4–8 Hz), alpha (10–16 Hz), and gamma (74–98 Hz) spectral windows were imaged using a beamforming approach. Whole-brain voxel-wise comparisons were then conducted on these dynamic functional maps to identify HIV-related differences in the neural oscillatory dynamics supporting cognitive flexibility. Our findings indicated group differences in alpha oscillatory activity in the cingulo-opercular cortices, and differences in gamma activity were found in the cerebellum. Across all participants, alpha and gamma activity in these regions were associated with performance on the cognitive flexibility task. Further, PWH who had been treated with antiretroviral therapy for a longer duration and those with higher current CD4 counts had alpha responses that more closely resembled those of seronegative controls, suggesting that optimal clinical management of HIV infection is associated with preserved neural dynamics supporting cognitive flexibility.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350674","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 : 2024-09-23DOI: 10.1016/j.nbd.2024.106679
Alzheimer's disease (AD) is characterized by progressive cognitive decline and neuropathological changes, yet the underlying neurobiological mechanisms remain elusive. Here, we employed a multimodal longitudinal neuroimaging approach, using anatomical and functional sequences on a high field magnetic resonance imaging (MRI) preclinical scanner, to investigate alterations in brain connectivity and white matter microstructure in a transgenic mouse model of AD (J20) when compared to wild-type (WT) littermates. Functional connectivity analysis revealed distinct network disruptions in J20 mice, primarily involving connections between posterior and anterior brain regions; importantly, a significant interaction between group and age highlighted an exacerbation of these connectivity changes with advancing age in J20 mice. In addition, significant reductions in fractional anisotropy (FA) were observed in the corpus callosum of J20 mice compared to WT, indicative of microstructural alterations consistent with white matter pathology. The observed alterations in brain connectivity and microstructure provide valuable insights into the spatiotemporal processes underlying AD-related decline and underscore the utility of multimodal neuroimaging in elucidating the neurobiological substrates of AD pathology in animal models.
{"title":"A longitudinal MRI analysis reveals altered brain connectivity and microstructural changes in a transgenic mouse model of Alzheimer's disease","authors":"","doi":"10.1016/j.nbd.2024.106679","DOIUrl":"10.1016/j.nbd.2024.106679","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is characterized by progressive cognitive decline and neuropathological changes, yet the underlying neurobiological mechanisms remain elusive. Here, we employed a multimodal longitudinal neuroimaging approach, using anatomical and functional sequences on a high field magnetic resonance imaging (MRI) preclinical scanner, to investigate alterations in brain connectivity and white matter microstructure in a transgenic mouse model of AD (J20) when compared to wild-type (WT) littermates. Functional connectivity analysis revealed distinct network disruptions in J20 mice, primarily involving connections between posterior and anterior brain regions; importantly, a significant interaction between group and age highlighted an exacerbation of these connectivity changes with advancing age in J20 mice. In addition, significant reductions in fractional anisotropy (FA) were observed in the corpus callosum of J20 mice compared to WT, indicative of microstructural alterations consistent with white matter pathology. The observed alterations in brain connectivity and microstructure provide valuable insights into the spatiotemporal processes underlying AD-related decline and underscore the utility of multimodal neuroimaging in elucidating the neurobiological substrates of AD pathology in animal models.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002791/pdfft?md5=43450098de98d9cbb9aa5700ef7ec892&pid=1-s2.0-S0969996124002791-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142316203","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}