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In Memoriam, Dr. Robert K. Yu. 谨以此纪念罗伯特·余博士。
IF 4.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2023-01-01 DOI: 10.1177/17590914221146888
Thomas N Seyfried, Yutaka Itokazu, Toshio Ariga, Erhard Bieberich
Dr. Robert K. Yu, affectionately known to most of his friends and colleagues as “Bob,” passed away peacefully on May 18, 2022, at the age of 84. Bob served as President of the American Society of Neurochemistry (ASN) from 2001 to 2003 where he instituted a number of foundational changes that improved membership and strengthened financial solvency (Figure 1). Bob received his BS in Chemistry from Tunghai University, Taiwan, in 1960. He received his PhD in Biochemistry from the University of Illinois Urbana/ Champaign in 1967 under the mentorship of Dr. Herbert E. Carter, a member of the National Academy of Sciences. Bob followed in the footsteps of his beloved and accomplished mother, Dr. June Yu, who graduated from the University of Illinois Urbana/Champaign with a PhD in Chemistry and was a pioneer as the first Chinese woman to receive a PhD in Chemistry in the US. Bob completed postdoctoral training in the Department of Neurology at the Albert Einstein College of Medicine/Yeshiva University from 1967 to 1972 under the mentorship of Dr. Robert W. Ledeen, a long-standing member of ASN. Bob began his long and distinguished scientific career as an Assistant Professor in the Departments of Neurology and Molecular Biology and Biochemistry at Yale University in 1973. Bob was rapidly promoted to tenured Professor where he worked until 1988. Bob received a Med. Sci. D. honorary degree from the University of Tokyo in 1980 and an M.A.H. honorary degree from Yale University in 1985. Bob was recruited as Chair and Professor of the Department of Biochemistry and Molecular Biophysics at the Medical College of Virginia/Virginia Commonwealth University. In 2000, Bob was recruited as Director and Professor of the Institute of Molecular Medicine and Genetics at the Medical College of Georgia and served in that capacity until 2009. He also served as President of the Society of Chinese Bioscientists in America from 2008 to 2010. He held the Chair of Georgia Research Alliance Eminent Scholar in Molecular and Cellular Neurobiology, and was the Founding Director of the Institute of Neuroscience at Georgia Health Sciences University, now Augusta University, until his death. Bob’s major research interests were in neurochemistry and developmental neurobiology, particularly as related to glcoconjugates in health and diseases. He published over 400 peer-reviewed scientific papers and served as a senior editor in several high-profile scientific journals including Journal of Lipid Research, Journal of Biological Chemistry, and ASN Neuro. Bob was widely regarded as a leader in the field of glycosphingolipid research. He widely supported the expansion of the Japan Oil Chemists’ Society. For over 40 years, he and his research teams characterized numerous glycosphingolipid structures and elucidated their biophysical properties, biosynthetic pathways, and biological functions. Bob and Dr. Robert Ledeen were the first to demonstrate that the naturally occurring sialidase-susceptib
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引用次数: 0
Sex and APOE Genotype Alter the Basal and Induced Inflammatory States of Primary Astrocytes from Humanized Targeted Replacement Mice. 性别和APOE基因型改变人源化靶向替代小鼠原发性星形胶质细胞的基础和诱导炎症状态。
IF 4.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2023-01-01 DOI: 10.1177/17590914221144549
Isha Mhatre-Winters, Aseel Eid, Yoonhee Han, Kim Tieu, Jason R Richardson

Apolipoprotein E4 (APOE4) genotype and sex are significant risk factors for Alzheimer's disease (AD), with females demonstrating increased risk modulated by APOE genotype. APOE is predominantly expressed in astrocytes, however, there is a lack of comprehensive assessments of sex differences in astrocytes stratified by APOE genotype. Here, we examined the response of mixed-sex and sex-specific neonatal APOE3 and APOE4 primary mouse astrocytes (PMA) to a cytokine mix of IL1b, TNFa, and IFNg. Pro-inflammatory and anti-inflammatory cytokine profiles were assessed by qRT-PCR and Meso Scale Discovery multiplex assay. Mixed-sex APOE4 PMA were found to have higher basal messenger RNA expression of several pro-inflammatory cytokines including Il6, Tnfa, Il1b, Mcp1, Mip1a, and Nos2 compared to APOE3 PMA, which was accompanied by increased levels of these secreted cytokines. In sex-specific cultures, basal expression of Il1b, Il6, and Nos2 was 1.5 to 2.5 fold higher in APOE4 female PMA compared to APOE4 males, with both being higher than APOE3 PMA. Similar results were found for secreted levels of these cytokines. Together, these findings indicate that APOE4 genotype and female sex, contribute to a greater inflammatory response in primary astrocytes and these data may provide a framework for investigating the mechanisms contributing to genotype and sex differences in AD-related neuroinflammation.

载脂蛋白E4 (APOE4)基因型和性别是阿尔茨海默病(AD)的重要危险因素,APOE基因型调节女性患病风险增加。APOE主要在星形胶质细胞中表达,然而,缺乏对APOE基因型分层星形胶质细胞性别差异的综合评估。在这里,我们研究了混合性别和性别特异性的新生儿APOE3和APOE4原代小鼠星形胶质细胞(PMA)对IL1b、TNFa和IFNg混合细胞因子的反应。通过qRT-PCR和Meso Scale Discovery多重检测评估促炎和抗炎细胞因子谱。与APOE3 PMA相比,混合性别APOE4 PMA具有更高的几种促炎细胞因子的基础信使RNA表达,包括Il6, Tnfa, Il1b, Mcp1, Mip1a和Nos2,并伴有这些分泌细胞因子的水平升高。在性别特异性培养中,与APOE4男性相比,APOE4女性PMA中Il1b, Il6和Nos2的基础表达量高出1.5至2.5倍,两者均高于APOE3 PMA。这些细胞因子的分泌水平也发现了类似的结果。总之,这些发现表明APOE4基因型和女性性别有助于原发性星形胶质细胞更大的炎症反应,这些数据可能为研究ad相关神经炎症中基因型和性别差异的机制提供框架。
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引用次数: 0
Thioredoxin-1 Promotes Mitochondrial Biogenesis Through Regulating AMPK/Sirt1/PGC1α Pathway in Alzheimer's Disease. 硫氧还蛋白-1通过调节AMPK/Sirt1/PGC1α通路促进阿尔茨海默病线粒体生物发生
IF 4.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2023-01-01 DOI: 10.1177/17590914231159226
Jinjing Jia, Jiayi Yin, Yu Zhang, Guangtao Xu, Min Wang, Haiying Jiang, Li Li, Xiansi Zeng, Dongsheng Zhu

Alzheimer's disease (AD) is the most common neurodegenerative disease. Increasing studies suggest that mitochondrial dysfunction is closely related to the pathogenesis of AD. Thioredoxin-1 (Trx-1), one of the major redox proteins in mammalian cells, plays neuroprotection in AD. However, whether Trx-1 could regulate the mitochondrial biogenesis in AD is largely unknown. In the present study, we found that Aβ25-35 treatment not only markedly induced excessive production of reactive oxygen species and apoptosis, but also significantly decreased the number of mitochondria with biological activity and the adenosine triphosphate content in mitochondria, suggesting mitochondrial biogenesis was impaired in AD cells. These changes were reversed by Lentivirus-mediated stable overexpression of Trx-1 or exogenous administration of recombinant human Trx-1. What's more, adeno-associated virus-mediated specific overexpression of Trx-1 in the hippocampus of β-amyloid precursor protein/presenilin 1 (APP/PS1) mice ameliorated the learning and memory and attenuated hippocampal Aβ deposition. Importantly, overexpression of Trx-1 in APP/PS1 mice restored the decrease in mitochondrial biogenesis-associated proteins, including adenosine monophosphate -activated protein kinase (AMPK), silent information regulator factor 2-related enzyme 1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). In addition, Lentivirus-mediated overexpression of Trx-1 in rat adrenal pheochromocytoma (PC12) cells also restored the decrease of AMPK, Sirt1, and PGC1α by Aβ25-35 treatment. Pharmacological inhibition of AMPK activity significantly abolished the effect of Trx-1 on mitochondrial biogenesis. Taken together, our data provide evidence that Trx-1 promoted mitochondrial biogenesis via restoring AMPK/Sirt1/PGC1α pathway in AD.

阿尔茨海默病(AD)是最常见的神经退行性疾病。越来越多的研究表明,线粒体功能障碍与AD的发病密切相关。Thioredoxin-1 (Trx-1)是哺乳动物细胞中主要的氧化还原蛋白之一,在AD中起神经保护作用。然而,Trx-1是否可以调节AD中线粒体的生物发生在很大程度上是未知的。在本研究中,我们发现Aβ25-35处理不仅显著诱导活性氧过量产生和细胞凋亡,而且显著减少线粒体中具有生物活性的线粒体数量和三磷酸腺苷含量,提示AD细胞线粒体生物发生受损。这些变化被慢病毒介导的Trx-1的稳定过表达或外源给药重组人Trx-1逆转。此外,腺相关病毒介导的Trx-1在APP/PS1小鼠海马区特异性过表达可改善学习记忆能力,减轻海马区Aβ沉积。重要的是,APP/PS1小鼠中Trx-1的过表达恢复了线粒体生物发生相关蛋白的减少,包括单磷酸腺苷活化蛋白激酶(AMPK)、沉默信息调节因子2相关酶1 (Sirt1)和过氧化物酶体增殖物激活受体γ辅助激活因子1- α (PGC1α)。此外,慢病毒介导的Trx-1在大鼠肾上腺嗜铬细胞瘤(PC12)细胞中的过表达也恢复了Aβ25-35处理后AMPK、Sirt1和PGC1α的下降。AMPK活性的药理抑制显著消除了Trx-1对线粒体生物发生的影响。综上所述,我们的数据提供了Trx-1通过恢复AD中AMPK/Sirt1/PGC1α通路促进线粒体生物发生的证据。
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引用次数: 1
An Association of Chitinase-3 Like-Protein-1 With Neuronal Deterioration in Multiple Sclerosis. 几丁质酶-3 类蛋白-1 与多发性硬化症神经元衰退的关系
IF 4.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2023-01-01 DOI: 10.1177/17590914231198980
Intakhar Ahmad, Stig Wergeland, Eystein Oveland, Lars Bø

Elevated levels of Chitinase-3-like protein-1 (CHI3L1) in cerebrospinal fluid have previously been linked to inflammatory activity and disease progression in multiple sclerosis (MS) patients. This study aimed to investigate the presence of CHI3L1 in the brains of MS patients and in the cuprizone model in mice (CPZ), a model of toxic/metabolic demyelination and remyelination in different brain areas. In MS gray matter (GM), CHI3L1 was detected primarily in astrocytes and in a subset of pyramidal neurons. In neurons, CHI3L1 immunopositivity was associated with lipofuscin-like substance accumulation, a sign of cellular aging that can lead to cell death. The density of CHI3L1-positive neurons was found to be significantly higher in normal-appearing MS GM tissue compared to that of control subjects (p  =  .014). In MS white matter (WM), CHI3L1 was detected in astrocytes located within lesion areas, as well as in perivascular normal-appearing areas and in phagocytic cells from the initial phases of lesion development. In the CPZ model, the density of CHI3L1-positive cells was strongly associated with microglial activation in the WM and choroid plexus inflammation. Compared to controls, CHI3L1 immunopositivity in WM was increased from an early phase of CPZ exposure. In the GM, CHI3L1 immunopositivity increased later in the CPZ exposure phase, particularly in the deep GM region. These results indicate that CHI3L1 is associated with neuronal deterioration, pre-lesion pathology, along with inflammation in MS.

甲壳素酶-3样蛋白-1(CHI3L1)在脑脊液中的水平升高与多发性硬化症(MS)患者的炎症活动和疾病进展有关。本研究旨在调查CHI3L1在多发性硬化症患者大脑和小鼠铜绿素模型(CPZ)中的存在情况,铜绿素模型是一种毒性/代谢性脱髓鞘和不同脑区再髓鞘化的模型。在多发性硬化症灰质(GM)中,主要在星形胶质细胞和锥体神经元亚群中检测到 CHI3L1。在神经元中,CHI3L1免疫阳性与脂褐素样物质的积累有关,脂褐素样物质是细胞衰老的标志,可导致细胞死亡。与对照组相比,正常表现的 MS GM 组织中 CHI3L1 阳性神经元的密度明显更高(p = .014)。在多发性硬化症白质(WM)中,位于病变区域内的星形胶质细胞、血管周围的正常外观区域以及病变发展初期的吞噬细胞中都检测到了 CHI3L1。在 CPZ 模型中,CHI3L1 阳性细胞的密度与 WM 中的小胶质细胞活化和脉络丛炎症密切相关。与对照组相比,CHI3L1在WM中的免疫阳性率从CPZ暴露的早期阶段就开始增加。在基因组中,CHI3L1免疫阳性反应在CPZ暴露阶段的后期增加,尤其是在基因组深部区域。这些结果表明,CHI3L1 与多发性硬化症的神经元退化、病变前病理和炎症有关。
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引用次数: 0
Casein Kinase 2 Mediates HIV- and Opioid-Induced Pathologic Phosphorylation of TAR DNA Binding Protein 43 in the Basal Ganglia. 酪蛋白激酶 2 在基底神经节介导 HIV 和阿片类药物诱导的 TAR DNA 结合蛋白 43 的病理性磷酸化。
IF 4.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2023-01-01 DOI: 10.1177/17590914231158218
Michael Ohene-Nyako, Sara R Nass, Hope T Richard, Robert Lukande, Melanie R Nicol, MaryPeace McRae, Pamela E Knapp, Kurt F Hauser

Summary statement: HIV/HIV-1 Tat and morphine independently increase pathologic phosphorylation of TAR DNA binding protein 43 in the striatum. HIV- and opioid-induced pathologic phosphorylation of TAR DNA binding protein 43 may involve enhanced CK2 activity and protein levels.

摘要说明:HIV/HIV-1 Tat 和吗啡可独立增加纹状体中 TAR DNA 结合蛋白 43 的病理性磷酸化。艾滋病毒和阿片类药物诱导的 TAR DNA 结合蛋白 43 的病理性磷酸化可能涉及 CK2 活性和蛋白水平的增强。
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引用次数: 0
Neuroprotection by Preconditioning in Mice is Dependent on MyD88-Mediated CXCL10 Expression in Endothelial Cells. 小鼠预处理的神经保护依赖于MyD88介导的CXCL10在内皮细胞中的表达。
IF 4.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2023-01-01 DOI: 10.1177/17590914221146365
Zhihong Chen, Weiwei Hu, Mynor J Mendez, Zachary C Gossman, Anthony Chomyk, Brendan T Boylan, Grahame J Kidd, Timothy W Phares, Cornelia C Bergmann, Bruce D Trapp

The central nervous system (CNS) can be preconditioned to resist damage by peripheral pretreatment with low-dose gram-negative bacterial endotoxin lipopolysaccharide (LPS). Underlying mechanisms associated with transient protection of the cerebral cortex against traumatic brain injury include increased neuronal production of antiapoptotic and neurotrophic molecules, microglial-mediated displacement of inhibitory presynaptic terminals innervating the soma of cortical projection neurons, and synchronized firing of cortical projection neurons. However, the cell types and signaling responsible for these neuronal and microglial changes are unknown. A fundamental question is whether LPS penetrates the CNS or acts on the luminal surface of brain endothelial cells, thereby triggering an indirect parenchymal neuroprotective response. The present study shows that a low-dose intraperitoneal LPS treatment increases brain endothelial cell activation markers CD54, but does not open the blood-brain barrier or alter brain endothelial cell tight junctions as assessed by electron microscopy. NanoString nCounter transcript analyses of CD31-positive brain endothelial cells further revealed significant upregulation of Cxcl10, C3, Ccl2, Il1β, Cxcl2, and Cxcl1, consistent with identification of myeloid differentiation primary response 88 (MyD88) as a regulator of these transcripts by pathway analysis. Conditional genetic endothelial cell gene ablation approaches demonstrated that both MyD88-dependent Toll-like receptor 4 (TLR4) signaling and Cxcl10 expression are essential for LPS-induced neuroprotection and microglial activation. These results suggest that C-X-C motif chemokine ligand 10 (CXCL10) production by endothelial cells in response to circulating TLR ligands may directly or indirectly signal to CXCR3 on neurons and/or microglia. Targeted activation of brain endothelial receptors may thus provide an attractive approach for inducing transient neuroprotection.

中枢神经系统(CNS)可以通过低剂量革兰氏阴性细菌内毒素脂多糖(LPS)的外周预处理来预处理以抵抗损伤。与大脑皮层对创伤性脑损伤的瞬时保护相关的潜在机制包括抗凋亡和神经营养分子的神经元产生增加,小胶质细胞介导的支配皮层投射神经元胞体的抑制性突触前终末的移位,以及皮层投射神经元的同步放电。然而,负责这些神经元和小胶质细胞变化的细胞类型和信号传导尚不清楚。一个根本问题是LPS是否穿透中枢神经系统或作用于脑内皮细胞的管腔表面,从而触发间接的实质神经保护反应。本研究表明,低剂量腹膜内LPS治疗增加了脑内皮细胞活化标志物CD54,但不会打开血脑屏障或改变脑内皮细胞紧密连接,如电子显微镜所评估的。CD31阳性脑内皮细胞的NanoString nCounter转录物分析进一步揭示了Cxcl10、C3、Ccl2、Il1β、Cxcl2和Cxcl1的显著上调,这与通过通路分析鉴定髓系分化初级反应88(MyD88)是这些转录物的调节剂相一致。条件遗传内皮细胞基因消融方法表明,MyD88依赖性Toll样受体4(TLR4)信号传导和Cxcl10表达对LPS诱导的神经保护和小胶质细胞活化至关重要。这些结果表明,内皮细胞响应循环TLR配体产生的C-X-C基序趋化因子配体10(CXCL10)可能直接或间接向神经元和/或小胶质细胞上的CXCR3发出信号。因此,脑内皮受体的靶向激活可以为诱导短暂的神经保护提供一种有吸引力的方法。
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引用次数: 0
Therapeutic Effect of Nicotinamide Mononucleotide for Hypoxic-Ischemic Brain Injury in Neonatal Mice. 烟酰胺单核苷酸对新生小鼠缺氧缺血性脑损伤的治疗作用。
IF 4.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2023-01-01 DOI: 10.1177/17590914231198983
Takuya Kawamura, Gagandeep Singh Mallah, Maryam Ardalan, Tetyana Chumak, Pernilla Svedin, Lina Jonsson, Seyedeh Marziyeh Jabbari Shiadeh, Fanny Goretta, Tomoaki Ikeda, Henrik Hagberg, Mats Sandberg, Carina Mallard

Summary statement: Neonatal hypoxia-ischemia reduces nicotinamide adenine dinucleotide (NAD+) and SIRT6 levels in the injured hippocampus.Hippocampal high mobility group box-1 (HMGB1) release is significantly increased after neonatal hypoxia-ischemia.Nicotinamide mononucleotide (NMN) treatment normalizes hippocampal NAD+ and SIRT6 levels, with significant decrease in caspase-3 activity and HMGB1 release.NMN improves early developmental behavior, as well as motor and memory function.

概述:新生儿缺氧缺血降低了受损海马中烟酰胺腺嘌呤二核苷酸(NAD+)和SIRT6的水平。新生儿缺氧缺血后,海马高迁移率组box-1(HMGB1)的释放显著增加。烟酰胺单核苷酸(NMN)治疗使海马NAD+和SIRT6水平正常化,胱天蛋白酶-3活性和HMGB1释放显著降低。NMN改善早期发育行为,以及运动和记忆功能。
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引用次数: 0
Transferrin Enhances Neuronal Differentiation. 转铁蛋白促进神经元分化。
IF 4.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2023-01-01 DOI: 10.1177/17590914231170703
María Julia Pérez, Tomas Roberto Carden, Paula Ayelen Dos Santos Claro, Susana Silberstein, Pablo Martin Páez, Veronica Teresita Cheli, Jorge Correale, Juana M Pasquini

Although transferrin (Tf) is a glycoprotein best known for its role in iron delivery, iron-independent functions have also been reported. Here, we assessed apoTf (aTf) treatment effects on Neuro-2a (N2a) cells, a mouse neuroblastoma cell line which, once differentiated, shares many properties with neurons, including process outgrowth, expression of selective neuronal markers, and electrical activity. We first examined the binding of Tf to its receptor (TfR) in our model and verified that, like neurons, N2a cells can internalize Tf from the culture medium. Next, studies on neuronal developmental parameters showed that Tf increases N2a survival through a decrease in apoptosis. Additionally, Tf accelerated the morphological development of N2a cells by promoting neurite outgrowth. These pro-differentiating effects were also observed in primary cultures of mouse cortical neurons treated with aTf, as neurons matured at a higher rate than controls and showed a decrease in the expression of early neuronal markers. Further experiments in iron-enriched and iron-deficient media showed that Tf preserved its pro-differentiation properties in N2a cells, with results hinting at a modulatory role for iron. Moreover, N2a-microglia co-cultures revealed an increase in IL-10 upon aTf treatment, which may be thought to favor N2a differentiation. Taken together, these findings suggest that Tf reduces cell death and favors the neuronal differentiation process, thus making Tf a promising candidate to be used in regenerative strategies for neurodegenerative diseases.

虽然转铁蛋白(Tf)是一种糖蛋白,以其在铁传递中的作用而闻名,但也有报道称其具有不依赖铁的功能。在这里,我们评估了apoTf (aTf)对神经-2a (N2a)细胞的治疗效果,神经-2a是一种小鼠神经母细胞瘤细胞系,一旦分化,与神经元共享许多特性,包括过程产物、选择性神经元标记物的表达和电活动。我们首先在我们的模型中检测了Tf与其受体(TfR)的结合,并验证了N2a细胞像神经元一样可以从培养基中内化Tf。接下来,对神经元发育参数的研究表明,Tf通过减少细胞凋亡来提高N2a的存活率。此外,Tf通过促进神经突的生长来加速N2a细胞的形态发育。在aTf处理的小鼠皮质神经元原代培养物中也观察到这些促进分化的作用,因为神经元的成熟速度高于对照组,并且早期神经元标记物的表达减少。在富铁和缺铁培养基中进行的进一步实验表明,Tf在N2a细胞中保持了其促分化特性,结果提示铁的调节作用。此外,N2a-小胶质细胞共培养显示,aTf处理后IL-10增加,这可能被认为有利于N2a分化。综上所述,这些发现表明Tf可以减少细胞死亡并促进神经元分化过程,因此使Tf成为一个有希望用于神经退行性疾病的再生策略的候选者。
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引用次数: 0
Dynamic Involvement of Striatal NG2-glia in L-DOPA Induced Dyskinesia in Parkinsonian Rats: Effects of Doxycycline. 左旋多巴诱导帕金森大鼠运动障碍时纹状体ng2神经胶质的动态参与:强力霉素的影响。
IF 4.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2023-01-01 DOI: 10.1177/17590914231155976
G C Nascimento, M Bortolanza, A Bribian, G C Leal-Luiz, R Raisman-Vozari, L López-Mascaraque, E Del-Bel

Summary statement: NG2-glia alters its dynamics in response to L-DOPA-induced dyskinesia. In these animals, striatal NG2-glia density was reduced with cells presenting activated phenotype while doxycycline antidyskinetic therapy promotes a return to NG2-glia cell density and protein to a not activated state.

摘要:ng2 -胶质细胞在左旋多巴诱导的运动障碍中改变其动力学。在这些动物中,纹状体ng2 -胶质细胞密度降低,细胞呈现激活表型,而强力霉素抗运动障碍治疗可促进ng2 -胶质细胞密度和蛋白质恢复到非激活状态。
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引用次数: 1
Expression of Ectonucleoside Triphosphate Diphosphohydrolase 2 (NTPDase2) Is Negatively Regulated Under Neuroinflammatory Conditions In Vivo and In Vitro 神经炎性条件下三磷酸二磷酸酶2(NTPDase2)表达的体内外负调控
IF 4.7 4区 医学 Q2 NEUROSCIENCES Pub Date : 2022-05-01 DOI: 10.1177/17590914221102068
M. Dragić, Katarina Mihajlović, Marija Adzic, Marija Jakovljevic, M. Z. Kontić, N. Mitrović, Danijela Laketa, I. Lavrnja, M. Kipp, I. Grković, N. Nedeljkovic
Ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2) hydrolyzes extracellular ATP to ADP, which is the ligand for P2Y1,12,13 receptors. The present study describes the distribution of NTPDase2 in adult rat brains in physiological conditions, and in hippocampal neurodegeneration induced by trimethyltin (TMT). The study also describes the regulation of NTPDase2 by inflammatory mediators in primary astrocytes and oligodendroglial cell line OLN93. In physiological conditions, NTPDase2 protein was most abundant in the hippocampus, where it was found in fibrous astrocytes and synaptic endings in the synaptic-rich hippocampal layers. In TMT-induced neurodegeneration, NTPDase2-mRNA acutely decreased at 2-dpi and then gradually recovered to the control level at 7-dpi and 21-dpi. As determined by immunohistochemistry and double immunofluorescence, the decrease was most pronounced in the dentate gyrus (DG), where NTPDase2 withdrew from the synaptic boutons in the polymorphic layer of DG, whereas the recovery of the expression was most profound in the subgranular layer. Concerning the regulation of NTPDase2 gene expression, proinflammatory cytokines IL-6, IL-1β, TNFα, and IFNγ negatively regulated the expression of NTPDase2 in OLN93 cells, while did not altering the expression in primary astrocytes. Different cell-intrinsic stressors, such as depletion of intracellular energy store, oxidative stress, endoplasmic reticulum stress, and activation of protein kinase C, also massively disturbed the expression of the NTPDase2 gene. Together, our results suggest that the expression and the activity of NTPDase2 transiently cease in neurodegeneration and brain injury, most likely as a part of the acute adaptive response designed to promote cell defense, survival, and recovery.
外核三磷酸二磷酸酶2(NTPDase2)将细胞外ATP水解为ADP,ADP是P2Y1、12、13受体的配体。本研究描述了NTPDase2在生理条件下成年大鼠大脑中的分布,以及在三甲基锡(TMT)诱导的海马神经退行性变中的分布。该研究还描述了原代星形胶质细胞和少突胶质细胞系OLN93中炎症介质对NTPDase2的调节。在生理条件下,NTPDase2蛋白在海马中含量最高,在富含突触的海马层的纤维星形胶质细胞和突触末梢中发现。在TMT诱导的神经退行性变中,NTPDase2mRNA在2-dpi时急剧下降,然后在7-dpi和21dpi时逐渐恢复到对照水平。通过免疫组织化学和双重免疫荧光测定,减少在齿状回(DG)最为明显,其中NTPDase2从DG多态层的突触突中退出,而表达在亚颗粒层的恢复最为深刻。关于NTPDase2基因表达的调节,促炎细胞因子IL-6、IL-1β、TNFα和IFNγ在OLN93细胞中负调节NTPDase2中的表达,而不改变原代星形胶质细胞中的表达。不同的细胞内在应激源,如细胞内能量储存的耗竭、氧化应激、内质网应激和蛋白激酶C的激活,也严重干扰NTPDase2基因的表达。总之,我们的研究结果表明,NTPDase2的表达和活性在神经退行性变和脑损伤中短暂停止,很可能是旨在促进细胞防御、存活和恢复的急性适应性反应的一部分。
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