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From metabolomics to proteomics: understanding the role of dopa decarboxylase in Parkinson’s disease. Scientific commentary on: “Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson’s disease” 从代谢组学到蛋白质组学:了解多巴脱羧酶在帕金森病中的作用。科学评论"脑脊液、血浆和尿液的综合蛋白质组学发现了早期帕金森病的多巴脱羧酶和其他生物标记物
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-05-18 DOI: 10.1007/s00401-024-02739-5
Nourhan Shebl, Mohamed Salama
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引用次数: 0
Tau filaments with the chronic traumatic encephalopathy fold in a case of vacuolar tauopathy with VCP mutation D395G 在一例VCP突变为D395G的空泡tau病病例中,Tau丝与慢性创伤性脑病折叠在一起
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-05-17 DOI: 10.1007/s00401-024-02741-x
Chao Qi, Ryota Kobayashi, Shinobu Kawakatsu, Fuyuki Kametani, Sjors H. W. Scheres, Michel Goedert, Masato Hasegawa

Dominantly inherited mutation D395G in the gene encoding valosin-containing protein causes vacuolar tauopathy, a type of behavioural-variant frontotemporal dementia, with marked vacuolation and abundant filamentous tau inclusions made of all six brain isoforms. Here we report that tau inclusions were concentrated in layers II/III of the frontotemporal cortex in a case of vacuolar tauopathy. By electron cryomicroscopy, tau filaments had the chronic traumatic encephalopathy (CTE) fold. Tau inclusions of vacuolar tauopathy share this cortical location and the tau fold with CTE, subacute sclerosing panencephalitis and amyotrophic lateral sclerosis/parkinsonism-dementia complex, which are believed to be environmentally induced. Vacuolar tauopathy is the first inherited disease with the CTE tau fold.

编码含缬氨酸蛋白的基因中的显性遗传突变 D395G 会导致空泡性 tau 病,这是一种行为变异型额颞叶痴呆症,具有明显的空泡化和丰富的丝状 tau 包涵体,由所有六种脑异构体组成。在这里,我们报告了一个空泡型tau病病例,其tau包涵体集中在额颞叶皮层的II/III层。通过电子冷冻显微镜观察,tau丝具有慢性创伤性脑病(CTE)的特征。空泡型tau蛋白病的tau包涵体与CTE、亚急性硬化性泛脑炎和肌萎缩性脊髓侧索硬化症/帕金森氏症-痴呆综合症具有相同的皮质位置和tau褶皱,这些疾病被认为是由环境诱发的。空泡型tau蛋白病是第一种具有CTE tau蛋白褶皱的遗传性疾病。
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引用次数: 0
Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors 全基因组杂合性缺失可预测垂体神经内分泌肿瘤的侵袭性和难治性行为
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-05-17 DOI: 10.1007/s00401-024-02736-8
Andrew L. Lin, Vasilisa A. Rudneva, Allison L. Richards, Yanming Zhang, Hyung Jun Woo, Marc Cohen, Jamie Tisnado, Nazanin Majd, Sharon L. Wardlaw, Gabrielle Page-Wilson, Soma Sengupta, Frances Chow, Bernard Goichot, Byram H. Ozer, Jorg Dietrich, Lisa Nachtigall, Arati Desai, Tina Alano, Shahiba Ogilive, David B. Solit, Tejus A. Bale, Marc Rosenblum, Mark T. A. Donoghue, Eliza B. Geer, Viviane Tabar

Pituitary neuroendocrine tumors (PitNETs) exhibiting aggressive, treatment-refractory behavior are the rare subset that progress after surgery, conventional medical therapies, and an initial course of radiation and are characterized by unrelenting growth and/or metastatic dissemination. Two groups of patients with PitNETs were sequenced: a prospective group of patients (n = 66) who consented to sequencing prior to surgery and a retrospective group (n = 26) comprised of aggressive/higher risk PitNETs. A higher mutational burden and fraction of loss of heterozygosity (LOH) was found in the aggressive, treatment-refractory PitNETs compared to the benign tumors (p = 1.3 × 10−10 and p = 8.5 × 10−9, respectively). Within the corticotroph lineage, a characteristic pattern of recurrent chromosomal LOH in 12 specific chromosomes was associated with treatment-refractoriness (occurring in 11 of 14 treatment-refractory versus 1 of 14 benign corticotroph PitNETs, p = 1.7 × 10−4). Across the cohort, a higher fraction of LOH was identified in tumors with TP53 mutations (p = 3.3 × 10−8). A machine learning approach identified loss of heterozygosity as the most predictive variable for aggressive, treatment-refractory behavior, outperforming the most common gene-level alteration, TP53, with an accuracy of 0.88 (95% CI: 0.70–0.96). Aggressive, treatment-refractory PitNETs are characterized by significant aneuploidy due to widespread chromosomal LOH, most prominently in the corticotroph tumors. This LOH predicts treatment-refractoriness with high accuracy and represents a novel biomarker for this poorly defined PitNET category.

垂体神经内分泌肿瘤(PitNET)具有侵袭性和难治性,是一种罕见的亚型肿瘤,在手术、常规药物治疗和初始放射治疗后仍有进展,其特点是持续生长和/或转移扩散。对两组PitNET患者进行了测序:一组是在手术前同意测序的前瞻性患者(66人),另一组是由侵袭性/高风险PitNET组成的回顾性患者(26人)。与良性肿瘤相比,侵袭性、难治性PitNET的突变负荷和杂合性缺失(LOH)比例更高(p = 1.3 × 10-10 和 p = 8.5 × 10-9)。在皮质营养细胞系中,12条特定染色体的复发性染色体LOH的特征模式与难治性相关(14例难治性PitNET中的11例与14例良性皮质营养细胞PitNET中的1例相关,p = 1.7 × 10-4)。在整个队列中,TP53突变的肿瘤中发现的LOH比例较高(p = 3.3 × 10-8)。机器学习方法发现,杂合性缺失是最具侵袭性、难治性行为的预测变量,其准确率为0.88(95% CI:0.70-0.96),高于最常见的基因水平改变TP53。具有侵袭性、难治性的PitNET因广泛的染色体LOH而具有显著的非整倍体特征,这在皮质营养瘤中最为突出。这种 LOH 预测难治性的准确率很高,是这一定义不清的 PitNET 类别的新型生物标记物。
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引用次数: 0
Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes Kii ALS/PDC 星形胶质细胞中异常的 CHCHD2 相关线粒体病变。
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-05-15 DOI: 10.1007/s00401-024-02734-w
Nicolas Leventoux, Satoru Morimoto, Mitsuru Ishikawa, Shiho Nakamura, Fumiko Ozawa, Reona Kobayashi, Hirotaka Watanabe, Sopak Supakul, Satoshi Okamoto, Zhi Zhou, Hiroya Kobayashi, Chris Kato, Yoshifumi Hirokawa, Ikuko Aiba, Shinichi Takahashi, Shinsuke Shibata, Masaki Takao, Mari Yoshida, Fumito Endo, Koji Yamanaka, Yasumasa Kokubo, Hideyuki Okano

Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson’s disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.

肌萎缩侧索硬化症/帕金森病-痴呆综合症(ALS/PDC)是一种罕见的复杂神经系统疾病,主要发生在西太平洋岛屿,包括日本、关岛和巴布亚地区。由于患者的症状与典型的肌萎缩侧索硬化症(ALS)或帕金森病(PD)相似,这种神秘的疾病一直备受医学界关注。与众不同的是,对患者大脑的尸检显示存在α-突触核蛋白聚集体和TDP-43,这分别是帕金森病和典型渐冻人症的特征。磷酸化 tau 的检测使这些观察结果变得更加复杂,突出了 ALS/PDC 蛋白病理的多面性。这种疾病的病因学基础仍未确定,遗传学研究也尚未给出结论性答案。不过,新出现的证据表明,维持大脑健康的关键细胞星形胶质细胞与神经退行性病变的发病有关,并可能在 ALS/PDC 的发病机制中发挥重要作用。利用先进的诱导多能干细胞技术,我们的团队培养了多个星形胶质细胞系,以进一步研究日本 ALS/PDC(Kii ALS/PDC)变异型。当疾病星形胶质细胞与健康对照组比较时,CHCHD2 成为一个明显失调的基因。我们的分析还揭示了特定通路激活的失衡:与星形胶质细胞纤毛功能障碍相关的通路(已知参与神经退行性变),以及与主要神经系统疾病(包括典型 ALS 和 PD)相关的通路。进一步的深入研究发现,受影响的星形胶质细胞的线粒体形态和代谢过程出现异常。一个特别引人注目的观察结果是,在 Kii ALS/PDC 患者的脊髓、运动皮层和眼球运动核中,CHCHD2 的表达减少。总之,我们的研究结果表明,Kii ALS/PDC星形胶质细胞对神经元的支持可能会减少,这强调了探索CHCHD2在维持线粒体健康方面的作用及其对该疾病的影响的必要性。
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引用次数: 0
Anaplastic histology and distinct molecular features in a small series of spinal cord ependymomas 一小批脊髓上皮瘤中的无弹性组织学和独特的分子特征。
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-05-12 DOI: 10.1007/s00401-024-02740-y
Ulrich Schüller, Antonia Gocke, Shweta Godbole, Claire Delbridge, Christian Thomas, Julia E. Neumann
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引用次数: 0
Physiological aging and inflammation-induced cellular senescence may contribute to oligodendroglial dysfunction in MS 生理衰老和炎症诱导的细胞衰老可能导致多发性硬化症的少突胶质细胞功能障碍
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-05-09 DOI: 10.1007/s00401-024-02733-x
Farina Windener, Laureen Grewing, Christian Thomas, Marie-France Dorion, Marie Otteken, Lara Kular, Maja Jagodic, Jack Antel, Stefanie Albrecht, Tanja Kuhlmann

Aging affects all cell types in the CNS and plays an important role in CNS diseases. However, the underlying molecular mechanisms driving these age-associated changes and their contribution to diseases are only poorly understood. The white matter in the aging brain as well as in diseases, such as Multiple sclerosis is characterized by subtle abnormalities in myelin sheaths and paranodes, suggesting that oligodendrocytes, the myelin-maintaining cells of the CNS, lose the capacity to preserve a proper myelin structure and potentially function in age and certain diseases. Here, we made use of directly converted oligodendrocytes (dchiOL) from young, adult and old human donors to study age-associated changes. dchiOL from all three age groups differentiated in an comparable manner into O4 + immature oligodendrocytes, but the proportion of MBP + mature dchiOL decreased with increasing donor age. This was associated with an increased ROS production and upregulation of cellular senescence markers such as CDKN1A, CDKN2A in old dchiOL. Comparison of the transcriptomic profiles of dchiOL from adult and old donors revealed 1324 differentially regulated genes with limited overlap with transcriptomic profiles of the donors’ fibroblasts or published data sets from directly converted human neurons or primary rodent oligodendroglial lineage cells. Methylome analyses of dchiOL and human white matter tissue samples demonstrate that chronological and epigenetic age correlate in CNS white matter as well as in dchiOL and resulted in the identification of an age-specific epigenetic signature. Furthermore, we observed an accelerated epigenetic aging of the myelinated, normal appearing white matter of multiple sclerosis (MS) patients compared to healthy individuals. Impaired differentiation and upregulation of cellular senescence markers could be induced in young dchiOL in vitro using supernatants from pro-inflammatory microglia. In summary, our data suggest that physiological aging as well as inflammation-induced cellular senescence contribute to oligodendroglial pathology in inflammatory demyelinating diseases such as MS.

衰老会影响中枢神经系统的所有细胞类型,并在中枢神经系统疾病中扮演重要角色。然而,人们对驱动这些年龄相关变化的潜在分子机制及其对疾病的影响还知之甚少。衰老脑白质以及多发性硬化症等疾病的特点是髓鞘和副髓鞘的细微异常,这表明中枢神经系统的髓鞘维持细胞少突胶质细胞在衰老和某些疾病中失去了保持适当髓鞘结构和潜在功能的能力。在这里,我们利用来自年轻人、成年人和老年人供体的直接转化少突胶质细胞(dchiOL)来研究与年龄相关的变化。所有三个年龄组的 dchiOL 都以类似的方式分化为 O4 + 未成熟少突胶质细胞,但 MBP + 成熟 dchiOL 的比例随着供体年龄的增加而下降。这与老龄 dchiOL 中 ROS 生成增加和细胞衰老标志物(如 CDKN1A、CDKN2A)上调有关。通过比较成年和老年供体的 dchiOL 转录组图谱,发现了 1324 个受不同调控的基因,这些基因与供体成纤维细胞的转录组图谱或已发表的直接转化人类神经元或原始啮齿类动物少突胶质细胞系细胞的转录组图谱重叠有限。对 dchiOL 和人类白质组织样本进行的甲基组分析表明,在中枢神经系统白质和 dchiOL 中,时间年龄和表观遗传年龄是相关的,并确定了年龄特异性表观遗传特征。此外,我们还观察到,与健康人相比,多发性硬化症(MS)患者有髓鞘、外观正常的白质表观遗传学老化加速。利用促炎性小胶质细胞的上清液可在体外诱导年轻的 dchiOL 分化受损和细胞衰老标记上调。总之,我们的数据表明,生理衰老和炎症诱导的细胞衰老是多发性硬化等炎症性脱髓鞘疾病少突胶质细胞病理学的原因。
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引用次数: 0
The shoulders we keep standing on: remembering Otto Marburg, a big brain in neurology and multiple sclerosis, at 150 我们不断站立的肩膀:缅怀神经学和多发性硬化症领域的巨匠奥托-马尔堡,享年 150 岁。
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-05-08 DOI: 10.1007/s00401-024-02717-x
Klaus Schmierer, Hans Lassmann
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引用次数: 0
Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex 结节性硬化症复合体内侧神经节突起神经元的 GABA 能调节受损和发育不成熟
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-05-07 DOI: 10.1007/s00401-024-02737-7
Mirte Scheper, Frederik N. F. Sørensen, Gabriele Ruffolo, Alessandro Gaeta, Lilian J. Lissner, Jasper J. Anink, Irina Korshunova, Floor E. Jansen, Kate Riney, Wim van Hecke, Angelika Mühlebner, Konstantin Khodosevich, Dirk Schubert, Eleonora Palma, James D. Mills, Eleonora Aronica

GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation–inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal NKCC1/KCC2 ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABAA receptor subunits, GABRA1, and upregulation of GABRA2. Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.

GABA 能中间神经元在维持神经回路平衡、兴奋-抑制调节和认知功能调节方面起着至关重要的作用。在结节性硬化症复合体(TSC)中,GABA能神经元功能障碍会导致网络活动紊乱和相关神经症状,这可能是一种细胞类型特异性方式。这项以GABA能神经元为中心的研究侧重于识别TSC中特定的中间神经元亚群,强调内侧神经节突起(MGE)和尾部神经节突起(CGE)衍生的中间神经元的独特性。通过对 TSC 患者材料进行单核 RNA 测序,我们发现表达体生长抑素(SST+)的中间神经元是 TSC 中一个独特的未成熟亚群。SST+中间神经元的成熟受到干扰,可能在发育过程中经历了从兴奋性到抑制性GABA能信号的不完全转换,从而导致抑制特性降低。值得注意的是,这项研究揭示了 SST+ 中间神经元的不成熟标记,包括异常的 NKCC1/KCC2 比率,表明对 GABA 能信号突触后后果至关重要的氯离子平衡失衡,以及 GABAA 受体亚基 GABRA1 的下调和 GABRA2 的上调。对SST+中间神经元的进一步研究发现,SST+中间神经元在TSC脑组织中的定位模式发生了改变,主要集中在较深的皮层,这可能与皮层分层障碍有关。在癫痫方面,我们的研究强调了GABA能中间神经元在形成癫痫发作中的不同细胞类型特异性作用,从而为精确治疗提供了依据。此外,这项研究还揭示了SST+中间神经元对TSC病理生理学的潜在贡献,为有针对性的治疗干预提供了启示。
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引用次数: 0
Sex differences in the extent of acute axonal pathologies after experimental concussion 实验性脑震荡后急性轴突病变程度的性别差异
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-05-05 DOI: 10.1007/s00401-024-02735-9
Hailong Song, Alexandra Tomasevich, Andrew Paolini, Kevin D. Browne, Kathryn L. Wofford, Brian Kelley, Eashwar Kantemneni, Justin Kennedy, Yue Qiu, Andrea L. C. Schneider, Jean-Pierre Dolle, D. Kacy Cullen, Douglas H. Smith

Although human females appear be at a higher risk of concussion and suffer worse outcomes than males, underlying mechanisms remain unclear. With increasing recognition that damage to white matter axons is a key pathologic substrate of concussion, we used a clinically relevant swine model of concussion to explore potential sex differences in the extent of axonal pathologies. At 24 h post-injury, female swine displayed a greater number of swollen axonal profiles and more widespread loss of axonal sodium channels than males. Axon degeneration for both sexes appeared to be related to individual axon architecture, reflected by a selective loss of small caliber axons after concussion. However, female brains had a higher percentage of small caliber axons, leading to more extensive axon loss after injury compared to males. Accordingly, sexual dimorphism in axonal size is associated with more extensive axonal pathology in females after concussion, which may contribute to worse outcomes.

虽然与男性相比,女性发生脑震荡的风险似乎更高,结果也更糟糕,但其潜在机制仍不清楚。随着越来越多的人认识到白质轴突损伤是脑震荡的一个关键病理基础,我们利用与临床相关的猪脑震荡模型来探讨轴突病变程度的潜在性别差异。受伤后24小时,雌性猪比雄性猪显示出更多的轴突肿胀轮廓和更广泛的轴突钠通道缺失。雌猪和雄猪的轴突退化似乎都与个体轴突结构有关,这反映在脑震荡后小口径轴突的选择性丢失上。然而,与男性相比,女性大脑中的小口径轴突比例更高,导致受伤后轴突损失更广泛。因此,轴突大小的性别二形性与女性脑震荡后更广泛的轴突病理学有关,这可能会导致更糟糕的后果。
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引用次数: 0
Characterisation of premature cell senescence in Alzheimer’s disease using single nuclear transcriptomics 利用单核转录组学分析阿尔茨海默病细胞早衰的特征
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-05-02 DOI: 10.1007/s00401-024-02727-9
Nurun N. Fancy, Amy M. Smith, Alessia Caramello, Stergios Tsartsalis, Karen Davey, Robert C. J. Muirhead, Aisling McGarry, Marion H. Jenkyns, Eleonore Schneegans, Vicky Chau, Michael Thomas, Sam Boulger, To Ka Dorcas Cheung, Emily Adair, Marianna Papageorgopoulou, Nanet Willumsen, Combiz Khozoie, Diego Gomez-Nicola, Johanna S. Jackson, Paul M. Matthews

Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer’s disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16INK4A (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater β-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for β-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased β-amyloid leading to premature senescence in microglia. We replicated these observations with independent AD snRNA-seq datasets. Our results describe a burden of senescent glia with AD that is sufficiently high to contribute to disease progression. These findings support the hypothesis that microglia are a primary target for senolytic treatments in AD.

衰老与细胞衰老有关,是阿尔茨海默病的主要风险因素。我们利用成像质谱细胞仪(IMC)和单核糖核酸(snRNA)测序(20 万个细胞核)研究了非患病对照组(NDC)和阿尔茨海默病(AD)供体死后大脑中细胞过早衰老的特征。我们发现,相对于 NDC,AD 患者神经胶质免疫染色半乳糖苷酶 beta(4 倍)和 p16INK4A(2 倍)的数量增加。衰老相关基因的胶质表达增加与β-淀粉样蛋白负荷增加有关。过早衰老的小胶质细胞下调了吞噬途径,这表明清除β淀粉样蛋白的能力下降。基因组富集和伪时间轨迹描述了与导致小胶质细胞过早衰老的β淀粉样蛋白增加相关的广泛DNA双链断裂(DSB)、线粒体功能障碍和ER应激。我们用独立的 AD snRNA-seq 数据集重复了这些观察结果。我们的研究结果表明,AD 患者的衰老胶质细胞负担很重,足以导致疾病进展。这些发现支持了小胶质细胞是AD衰老治疗的主要靶点这一假设。
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引用次数: 0
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Acta Neuropathologica
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