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Cerebrospinal fluid cyclase-associated protein 2 is increased in Alzheimer's disease and correlates with tau pathology. 脑脊液环化酶相关蛋白2在阿尔茨海默病中升高并与tau病理相关。
IF 10.8 1区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-16 DOI: 10.1186/s40035-024-00462-5
Alessandro Padovani, Andrea Pilotto, Silvia Pelucchi, Laura D'Andrea, Ramona Stringhi, Federica Gorla, Bahar Aksan, Salvatore Caratozzolo, Alberto Benussi, Alice Galli, Clara Tirloni, Daniela Mauceri, Antonio Canale, Silvana Archetti, Barbara Borroni, Monica Di Luca, Elena Marcello
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引用次数: 0
Peripheral proteinopathy in neurodegenerative diseases. 神经退行性疾病中的外周蛋白病。
IF 10.8 1区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-16 DOI: 10.1186/s40035-024-00461-6
Bin Xu, Xia Lei, Ying Yang, Jiayi Yu, Jun Chen, Zhi Xu, Keqiang Ye, Jing Zhang

Proteinopathies in neurology typically refer to pathological changes in proteins associated with neurological diseases, such as the aggregation of amyloid β and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease and multiple system atrophy, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal dementia. Interestingly, these proteins are also commonly found in peripheral tissues, raising important questions about their roles in neurological disorders. Multiple studies have shown that peripherally derived pathological proteins not only travel to the brain through various routes, aggravating brain pathology, but also contribute significantly to peripheral dysfunction, highlighting their crucial impact on neurological diseases. Investigating how these peripherally derived proteins influence the progression of neurological disorders could open new horizons for achieving early diagnosis and treatment. This review summarizes the distribution, transportation pathways, and pathogenic mechanisms of several neurodegenerative disease-related pathological proteins in the periphery, proposing that targeting these peripheral pathological proteins could be a promising strategy for preventing and managing neurological diseases.

神经学中的蛋白质病变通常是指与神经系统疾病相关的蛋白质的病理改变,如阿尔茨海默病中淀粉样蛋白β和Tau的聚集,帕金森病和多系统萎缩中的α-突触核蛋白,肌萎缩侧索硬化症和额颞叶痴呆中的TAR dna结合蛋白43。有趣的是,这些蛋白质也普遍存在于外周组织中,这就提出了它们在神经系统疾病中所起作用的重要问题。多项研究表明,外周来源的病理蛋白不仅通过多种途径进入大脑,加重大脑病理,而且还对外周功能障碍有重要贡献,突出了它们在神经系统疾病中的重要作用。研究这些外周来源的蛋白质如何影响神经系统疾病的进展,可以为实现早期诊断和治疗开辟新的视野。本文综述了几种神经退行性疾病相关的外周病理蛋白的分布、转运途径和致病机制,提出靶向这些外周病理蛋白可能是预防和治疗神经系统疾病的一种有前途的策略。
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引用次数: 0
N-terminus α-synuclein detection reveals new and more diverse aggregate morphologies in multiple system atrophy and Parkinson's disease. n端α-突触核蛋白检测揭示了多系统萎缩和帕金森病中新的和更多样化的聚集形态。
IF 10.8 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-27 DOI: 10.1186/s40035-024-00456-3
James A Wiseman, YuHong Fu, Richard L M Faull, Clinton P Turner, Maurice A Curtis, Glenda M Halliday, Birger V Dieriks

Background: Parkinson's disease (PD) and multiple system atrophy (MSA) are classified as α-synucleinopathies and are primarily differentiated by their clinical phenotypes. Delineating these diseases based on their specific α-synuclein (α-Syn) proteoform pathologies is crucial for accurate antemortem biomarker diagnosis. Newly identified α-Syn pathologies in PD raise questions about whether MSA exhibits a similar diversity. This prompted the need for a comparative study focusing on α-Syn epitope-specific immunoreactivities in both diseases, which could clarify the extent of pathological overlap and diversity, and guide more accurate biomarker development.

Methods: We utilised a multiplex immunohistochemical approach to detect multiple structural domains of α-Syn proteoforms across multiple regions prone to pathological accumulation in MSA (n = 10) and PD (n = 10). Comparison of epitope-specific α-Syn proteoforms was performed in the MSA medulla, inferior olivary nucleus, substantia nigra, hippocampus, and cerebellum, and in the PD olfactory bulb, medulla, substantia nigra, hippocampus, and entorhinal cortex.

Results: N-terminus and C-terminus antibodies detected significantly more α-Syn pathology in MSA than antibodies for phosphorylated (pS129) α-Syn, which are classically used to detect α-Syn. Importantly, C-terminus immunolabelling is more pronounced in MSA compared to PD. Meanwhile, N-terminus immunolabelling consistently detected the highest percentage of α-Syn across pathologically burdened regions of both diseases, which could be of biological significance. As expected, oligodendroglial involvement distinguished MSA from PD, but in contrast to PD, no substantial astrocytic or microglial α-Syn accumulation in MSA occurred. These data confirm glial-specific changes between these diseases when immunolabelling the N-terminus epitope. In comparison, N-terminus neuronal α-Syn was present in PD and MSA, with most MSA neurons lacking pS129 α-Syn proteoforms. This explains why characterisation of neuronal MSA pathologies is lacking and challenges the reliance on pS129 antibodies for the accurate quantification of α-Syn pathological load across α-synucleinopathies.

Conclusions: These findings underscore the necessity of utilising a multiplex approach to detect α-Syn, most importantly including the N-terminus, to capture the entire spectrum of α-Syn proteoforms in α-synucleinopathies. The data provide novel insights toward the biological differentiation of these α-synucleinopathies and pave the way for more refined antemortem diagnostic methods to facilitate early identification and intervention of these neurodegenerative diseases.

背景:帕金森病(PD)和多系统萎缩(MSA)被归类为α-突触核蛋白病,主要通过其临床表型进行区分。根据特定的α-突触核蛋白(α-Syn)蛋白形态病理来描述这些疾病对于准确的生前生物标志物诊断至关重要。新近发现的PD中α-Syn病理引发了MSA是否具有类似多样性的问题。这提示有必要对两种疾病的α-Syn表位特异性免疫反应性进行比较研究,以澄清病理重叠和多样性的程度,并指导更准确的生物标志物开发。方法:采用多重免疫组织化学方法检测MSA (n = 10)和PD (n = 10)中多个容易病理积累的区域α-Syn蛋白形成的多个结构域。比较MSA髓质、下橄榄核、黑质、海马和小脑以及PD嗅球、髓质、黑质、海马和内嗅皮层中表位特异性α-Syn蛋白形态。结果:与磷酸化(pS129) α-Syn抗体相比,n端和c端抗体在MSA中检测α-Syn的病理变化明显高于α-Syn抗体。重要的是,与PD相比,MSA中c端免疫标记更为明显。同时,n端免疫标记在两种疾病的病理负担区均检测到最高比例的α-Syn,这可能具有生物学意义。正如预期的那样,少突胶质细胞的受累将MSA与PD区分开来,但与PD相反,MSA中没有出现大量星形细胞或小胶质细胞α-Syn积累。当免疫标记n端表位时,这些数据证实了这些疾病之间胶质细胞特异性的变化。PD和MSA中均存在n端神经元α-Syn, MSA中多数神经元缺乏pS129 α-Syn蛋白形态。这解释了为什么缺乏神经元MSA病理特征,并挑战了对pS129抗体的依赖,以准确定量α-突触核蛋白病的α-Syn病理负荷。结论:这些发现强调了利用多重方法检测α-Syn的必要性,最重要的是包括n端,以捕获α-突触核蛋白病中α-Syn蛋白形式的整个谱。这些数据为这些α-突触核蛋白病的生物学分化提供了新的见解,并为更精细的生前诊断方法铺平了道路,以促进这些神经退行性疾病的早期识别和干预。
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引用次数: 0
SARS-CoV-2 membrane protein induces neurodegeneration via affecting Golgi-mitochondria interaction. SARS-CoV-2膜蛋白通过影响高尔基-线粒体相互作用诱导神经变性。
IF 10.8 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-27 DOI: 10.1186/s40035-024-00458-1
Fang Wang, Hailong Han, Caifang Wang, Jingfei Wang, Yanni Peng, Ye Chen, Yaohui He, Zhouyang Deng, Fang Li, Yikang Rong, Danling Wang, Wen Liu, Hualan Chen, Zhuohua Zhang

Background: Neurological complications are a significant concern of Coronavirus Disease 2019 (COVID-19). However, the pathogenic mechanism of neurological symptoms associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is poorly understood.

Methods: We used Drosophila as a model to systematically analyze SARS-CoV-2 genes encoding structural and accessory proteins and identified the membrane protein (M) that disrupted mitochondrial functions in vivo. The M protein was stereotaxically injected to further assess its effects in the brains of wild-type (WT) and 5 × FAD mice. Omics technologies, including RNA sequencing and interactome analysis, were performed to explore the mechanisms of the effects of M protein both in vitro and in vivo.

Results: Systematic analysis of SARS-CoV-2 structural and accessory proteins in Drosophila identified that the M protein induces mitochondrial fragmentation and dysfunction, leading to reduced ATP production, ROS overproduction, and eventually cell death in the indirect flight muscles. In WT mice, M caused hippocampal atrophy, neural apoptosis, glial activation, and mitochondrial damage. These changes were further aggravated in 5 × FAD mice. M was localized to the Golgi apparatus and genetically interacted with four wheel drive (FWD, a Drosophila homolog of mammalian PI4KIIIβ) to regulate Golgi functions in flies. Fwd RNAi, but not PI4KIIIα RNAi, reversed the M-induced Golgi abnormality, mitochondrial fragmentation, and ATP reduction. Inhibition of PI4KIIIβ activity suppressed the M-induced neuronal cell death. Therefore, M induced mitochondrial fragmentation and apoptosis likely through disruption of Golgi-derived PI(4)P-containing vesicles.

Conclusions: M disturbs the distribution and function of Golgi, leading to mitochondrial abnormality and eventually neurodegeneration via a PI4KIIIβ-mediated mechanism. This study reveals a potential mechanism for COVID-19 neurological symptoms and opens a new avenue for development of therapeutic strategies targeting SARS-CoV-2 M or mitochondria.

背景:神经系统并发症是2019冠状病毒病(COVID-19)的一个重要问题。然而,与严重急性呼吸综合征冠状病毒2 (SARS-CoV-2)感染相关的神经症状的致病机制尚不清楚。方法:以果蝇为模型,系统分析编码结构蛋白和辅助蛋白的SARS-CoV-2基因,鉴定体内破坏线粒体功能的膜蛋白(M)。通过立体定向注射M蛋白,进一步评估其在野生型(WT)和5 × FAD小鼠脑内的作用。采用组学技术,包括RNA测序和相互作用组分析,探索M蛋白在体外和体内的作用机制。结果:对果蝇中SARS-CoV-2结构蛋白和辅助蛋白的系统分析发现,M蛋白诱导线粒体断裂和功能障碍,导致间接飞行肌中ATP产生减少,ROS产生过剩,最终导致细胞死亡。在WT小鼠中,M引起海马萎缩、神经细胞凋亡、胶质细胞激活和线粒体损伤。这些变化在5 × FAD小鼠中进一步加重。M定位于高尔基体,并与四轮驱动(FWD,哺乳动物pi4kii β的果蝇同源物)基因相互作用,调节果蝇的高尔基体功能。Fwd RNAi,而非pi4kii α RNAi,逆转了m诱导的高尔基体异常、线粒体断裂和ATP减少。抑制pi4kii β活性可抑制m诱导的神经元细胞死亡。因此,M可能通过破坏高尔基衍生的PI(4) p -囊泡诱导线粒体断裂和凋亡。结论:M通过pi4kii β介导的机制干扰高尔基体的分布和功能,导致线粒体异常,最终导致神经退行性变。该研究揭示了COVID-19神经症状的潜在机制,为开发针对sars - cov - 2m或线粒体的治疗策略开辟了新的途径。
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引用次数: 0
Endosomal traffic disorders: a driving force behind neurodegenerative diseases. 内体交通紊乱:神经退行性疾病背后的驱动力。
IF 10.8 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-24 DOI: 10.1186/s40035-024-00460-7
Jianru Dong, Weiwei Tong, Mingyan Liu, Mengyu Liu, Jinyue Liu, Xin Jin, Ju Chen, Huachao Jia, Menglin Gao, Minjie Wei, Ying Duan, Xin Zhong

Endosomes are crucial sites for intracellular material sorting and transportation. Endosomal transport is a critical process involved in the selective uptake, processing, and intracellular transport of substances. The equilibrium between endocytosis and circulation mediated by the endosome-centered transport pathway plays a significant role in cell homeostasis, signal transduction, and immune response. In recent years, there have been hints linking endosomal transport abnormalities to neurodegenerative diseases, including Alzheimer's disease. Nonetheless, the related mechanisms remain unclear. Here, we provide an overview of endosomal-centered transport pathways and highlight potential physiological processes regulated by these pathways, with a particular focus on the correlation of endosomal trafficking disorders with common pathological features of neurodegenerative diseases. Additionally, we summarize potential therapeutic agents targeting endosomal trafficking for the treatment of neurodegenerative diseases.

核内体是细胞内物质分选和运输的关键部位。内体转运是参与物质选择性摄取、加工和细胞内转运的关键过程。内吞作用与循环之间的平衡是由内核转运途径介导的,在细胞稳态、信号转导和免疫应答中起着重要作用。近年来,有迹象表明内体转运异常与神经退行性疾病,包括阿尔茨海默病有关。尽管如此,相关机制仍不清楚。在这里,我们概述了以内体为中心的转运途径,并强调了由这些途径调节的潜在生理过程,特别关注内体转运障碍与神经退行性疾病的常见病理特征的相关性。此外,我们总结了潜在的治疗药物靶向内体运输治疗神经退行性疾病。
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引用次数: 0
Inflammasomes in neurodegenerative diseases. 神经退行性疾病中的炎性小体。
IF 10.8 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-23 DOI: 10.1186/s40035-024-00459-0
Qianchen Wang, Songwei Yang, Xuan Zhang, Shanshan Zhang, Liping Chen, Wanxue Wang, Naihong Chen, Jiaqing Yan

Inflammasomes represent a crucial component of the innate immune system, which respond to threats by recognizing different molecules. These are known as pathogen-associated molecular patterns (PAMPs) or host-derived damage-associated molecular patterns (DAMPs). In neurodegenerative diseases and neuroinflammation, the accumulation of misfolded proteins, such as beta-amyloid and alpha-synuclein, can lead to inflammasome activation, resulting in the release of interleukin (IL)-1β and IL-18. This activation also induces pyroptosis, the release of inflammatory mediators, and exacerbates neuroinflammation. Increasing evidence suggests that inflammasomes play a pivotal role in neurodegenerative diseases. Therefore, elucidating and investigating the activation and regulation of inflammasomes in these diseases is of paramount importance. This review is primarily focused on evidence indicating that inflammasomes are activated through the canonical pathway in these diseases. Inflammasomes as potential targets for treating neurodegenerative diseases are also discussed.

炎性小体是先天免疫系统的一个重要组成部分,它通过识别不同的分子来应对威胁。这些被称为病原体相关分子模式(PAMPs)或宿主源性损伤相关分子模式(DAMPs)。在神经退行性疾病和神经炎症中,错误折叠蛋白(如β -淀粉样蛋白和α -突触核蛋白)的积累可导致炎性体激活,导致白细胞介素(IL)-1β和IL-18的释放。这种激活还会诱发焦亡,释放炎症介质,并加剧神经炎症。越来越多的证据表明,炎症小体在神经退行性疾病中起着关键作用。因此,阐明和研究炎症小体在这些疾病中的激活和调节是至关重要的。本综述主要关注炎症小体在这些疾病中通过典型途径被激活的证据。炎性小体作为治疗神经退行性疾病的潜在靶点也进行了讨论。
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引用次数: 0
CD2AP deficiency aggravates Alzheimer's disease phenotypes and pathology through p38 MAPK activation. CD2AP缺乏通过p38 MAPK激活加重阿尔茨海默病的表型和病理。
IF 10.8 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-19 DOI: 10.1186/s40035-024-00454-5
Yan-Yan Xue, Zhe-Sheng Zhang, Rong-Rong Lin, Hui-Fen Huang, Ke-Qing Zhu, Dian-Fu Chen, Zhi-Ying Wu, Qing-Qing Tao

Background: Alzheimer's disease (AD) is the most common form of neurodegenerative disorder, which is characterized by a decline in cognitive abilities. Genome-wide association and clinicopathological studies have demonstrated that the CD2-associated protein (CD2AP) gene is one of the most important genetic risk factors for AD. However, the precise mechanisms by which CD2AP is linked to AD pathogenesis remain unclear.

Methods: The spatiotemporal expression pattern of CD2AP was determined. Then, we generated and characterized an APP/PS1 mouse model with neuron-specific Cd2ap deletion, using immunoblotting, immunofluorescence, enzyme-linked immunosorbent assay, electrophysiology and behavioral tests. Additionally, we established a stable CD2AP-knockdown SH-SY5Y cell line to further elucidate the specific molecular mechanisms by which CD2AP contributes to AD pathogenesis. Finally, the APP/PS1 mice with neuron-specific Cd2ap deletion were treated with an inhibitor targeting the pathway identified above to further validate our findings.

Results: CD2AP is widely expressed in various regions of the mouse brain, with predominant expression in neurons and vascular endothelial cells. In APP/PS1 mice, neuronal knockout of Cd2ap significantly aggravated tau pathology, synaptic impairments and cognitive deficits. Mechanistically, the knockout of Cd2ap activated p38 mitogen-activated protein kinase (MAPK) signaling, which contributed to increased tau phosphorylation, synaptic injury, neuronal apoptosis and cognitive impairment. Furthermore, the phenotypes of neuronal Cd2ap knockout were ameliorated by a p38 MAPK inhibitor.

Conclusion: Our study presents the first in vivo evidence that CD2AP deficiency exacerbates the phenotypes and pathology of AD through the p38 MAPK pathway, identifying CD2AP/p38 MAPK as promising therapeutic targets for AD.

背景:阿尔茨海默病(AD)是最常见的神经退行性疾病,其特征是认知能力下降。全基因组关联和临床病理研究表明,cd2相关蛋白(CD2AP)基因是阿尔茨海默病最重要的遗传危险因素之一。然而,CD2AP与AD发病机制相关的确切机制尚不清楚。方法:测定CD2AP的时空表达模式。然后,我们通过免疫印迹、免疫荧光、酶联免疫吸附试验、电生理和行为测试,建立了神经元特异性Cd2ap缺失的APP/PS1小鼠模型并对其进行了表征。此外,我们建立了稳定的CD2AP敲低SH-SY5Y细胞系,以进一步阐明CD2AP参与AD发病的具体分子机制。最后,用靶向上述途径的抑制剂处理神经元特异性Cd2ap缺失的APP/PS1小鼠,以进一步验证我们的发现。结果:CD2AP在小鼠脑各区域广泛表达,主要表达于神经元和血管内皮细胞。在APP/PS1小鼠中,Cd2ap的神经元敲除显著加重了tau病理、突触损伤和认知缺陷。从机制上讲,敲除Cd2ap激活了p38丝裂原活化蛋白激酶(MAPK)信号,导致tau磷酸化增加、突触损伤、神经元凋亡和认知障碍。此外,p38 MAPK抑制剂可改善神经元Cd2ap敲除的表型。结论:我们的研究首次提供了体内证据,证明CD2AP缺乏通过p38 MAPK途径加剧了AD的表型和病理,确定了CD2AP/p38 MAPK是AD的有希望的治疗靶点。
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引用次数: 0
Recombinant SMN protein synergizes with spinal muscular atrophy therapy to counteract pathological motor neuron phenotypes. 重组 SMN 蛋白与脊髓性肌萎缩症疗法协同作用,可抵消病理运动神经元表型。
IF 10.8 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-17 DOI: 10.1186/s40035-024-00455-4
Liliana Brambilla, Chiara F Valori, Giulia Guidotti, Francesca Martorana, Claudia Sulmona, Lisa Benedetta De Martini, Anselmo Canciani, Marco Fumagalli, Francesca Talpo, Gerardo Biella, Elisa Di Pasquale, Claudio Iacobucci, Federico Forneris, Haiyan Zhou, Daniela Rossi
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引用次数: 0
Astrocytes contribute to toll-like receptor 2-mediated neurodegeneration and alpha-synuclein pathology in a human midbrain Parkinson's model. 在人类中脑帕金森病模型中,星形胶质细胞促成了toll样受体2介导的神经退行性变和α-突触核蛋白病理学。
IF 10.8 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-16 DOI: 10.1186/s40035-024-00448-3
Fiona Weiss, Laura Hughes, Yuhong Fu, Cedric Bardy, Glenda M Halliday, Nicolas Dzamko

Background: Parkinson's disease (PD) is characterised by degeneration of ventral midbrain dopaminergic (DA) neurons and abnormal deposition of α-synuclein (α-syn) in neurons. Activation of the innate immune pathogen recognition receptor toll-like receptor 2 (TLR2) is associated with exacerbation of α-syn pathology. TLR2 is increased on neurons in the PD brain, and its activation results in the accumulation and propagation of α-syn through autophagy inhibition in neurons. In addition to the aggregation and propagation of pathological α-syn, dysfunction of astrocytes may contribute to DA neuronal death and subsequent clinical progression of PD. However, the role of astrocytes in TLR2-mediated PD pathology is less explored but important to address, given that TLR2 is a potential therapeutic target for PD.

Methods: Induced pluripotent stem cells from three controls and three PD patients were differentiated into a midbrain model comprised of neurons (including DA neurons) and astrocytes. Cells were treated with or without the TLR2 agonist Pam3CSK4, and α-syn pathology was seeded using pre-formed fibrils. Confocal imaging was used to assess lysosomal function and α-syn pathology in the different cell types, as well as DA neuron health and astrocyte activation.

Results: TLR2 activation acutely impaired the autophagy lysosomal pathway, and potentiated α-syn pathology seeded by pre-formed fibrils in PD neurons and astrocytes, leading to degeneration and loss of DA neurons. The astrocytes displayed impaired chaperone-mediated autophagy reducing their ability to clear accumulated α-syn, and increases of A1 neurotoxic phenotypic proteins SerpinG1, complement C3, PSMB8 and GBP2. Moreover, the phenotypic changes in astrocytes correlated with a specific loss of DA neurons.

Conclusions: Taken together, these results support a role for astrocyte dysfunction in α-syn accumulation and DA neuronal loss following TLR2 activation in PD.

背景:帕金森病(PD)以中脑腹侧多巴胺能(DA)神经元变性和神经元中α-突触核蛋白(α-syn)异常沉积为特征。先天免疫病原体识别受体toll样受体2 (TLR2)的激活与α-syn病理恶化有关。PD脑神经元上TLR2增加,其激活通过抑制神经元自噬导致α-syn的积累和增殖。除了病理性α-syn的聚集和增殖外,星形胶质细胞的功能障碍可能导致DA神经元死亡和PD的临床进展。然而,星形胶质细胞在TLR2介导的PD病理中的作用研究较少,但考虑到TLR2是PD的潜在治疗靶点,这一点很重要。方法:将3例对照组和3例PD患者的诱导多能干细胞分化成由神经元(包括DA神经元)和星形胶质细胞组成的中脑模型。用TLR2激动剂Pam3CSK4或不加TLR2激动剂Pam3CSK4处理细胞,用预先形成的原纤维播种α-syn病理。采用共聚焦成像技术评估不同细胞类型的溶酶体功能和α-syn病理,以及DA神经元健康和星形胶质细胞活化。结果:TLR2激活可严重破坏PD神经元和星形胶质细胞自噬溶酶体通路,增强PD神经元和星形胶质细胞中预形成原纤维播撒的α-syn病理,导致DA神经元变性和丢失。星形胶质细胞显示伴侣介导的自噬受损,清除积累的α-syn的能力降低,A1神经毒性表型蛋白SerpinG1、补体C3、PSMB8和GBP2增加。此外,星形胶质细胞的表型变化与DA神经元的特异性损失相关。结论:综上所述,这些结果支持星形胶质细胞功能障碍在PD患者TLR2激活后α-syn积累和DA神经元丢失中的作用。
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引用次数: 0
Cellular senescence as a key contributor to secondary neurodegeneration in traumatic brain injury and stroke. 细胞衰老是外伤性脑损伤和中风继发性神经变性的关键因素。
IF 10.8 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-12 DOI: 10.1186/s40035-024-00457-2
Zhihai Huang, Peisheng Xu, David C Hess, Quanguang Zhang

Traumatic brain injury (TBI) and stroke pose major health challenges, impacting millions of individuals globally. Once considered solely acute events, these neurological conditions are now recognized as enduring pathological processes with long-term consequences, including an increased susceptibility to neurodegeneration. However, effective strategies to counteract their devastating consequences are still lacking. Cellular senescence, marked by irreversible cell-cycle arrest, is emerging as a crucial factor in various neurodegenerative diseases. Recent research further reveals that cellular senescence may be a potential driver for secondary neurodegeneration following brain injury. Herein, we synthesize emerging evidence that TBI and stroke drive the accumulation of senescent cells in the brain. The rationale for targeting senescent cells as a therapeutic approach to combat neurodegeneration following TBI/stroke is outlined. From a translational perspective, we emphasize current knowledge and future directions of senolytic therapy for these neurological conditions.

创伤性脑损伤(TBI)和中风构成了重大的健康挑战,影响着全球数百万人。这些神经系统疾病曾经被认为是单纯的急性事件,现在被认为是具有长期后果的持久病理过程,包括对神经变性的易感性增加。然而,仍然缺乏有效的战略来抵消其破坏性后果。细胞衰老,以不可逆的细胞周期阻滞为标志,正在成为各种神经退行性疾病的关键因素。最近的研究进一步表明,细胞衰老可能是脑损伤后继发性神经变性的潜在驱动因素。在此,我们综合了TBI和中风驱动大脑中衰老细胞积累的新证据。本文概述了靶向衰老细胞作为TBI/卒中后神经退行性变的治疗方法的基本原理。从翻译的角度来看,我们强调这些神经系统疾病的当前知识和未来的治疗方向。
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引用次数: 0
期刊
Translational Neurodegeneration
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