Molecular and Cellular Neuroscience最新文献_第6页

Sex-specific cognitive benefits and anti-inflammatory effects of coumestrol pretreatment in transient global cerebral ischemia 谷美醇预处理在短暂性全脑缺血中的性别特异性认知益处和抗炎作用。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-01-15 DOI: 10.1016/j.mcn.2025.103991

Cibele Canal Castro , Adriana Vizuete , Bruna Ferrary Deniz , Angela Wyse , Carlos Alexandre Netto

Cerebral Global Ischemia (CGI) is a devastating neurological condition affecting millions globally each year, leading to significant inflammatory responses and long-term consequences, including delayed neuronal death and neurocognitive impairment. Following brain injury, resident microglial cells are activated, triggering pro-inflammatory cytokine expression and altering neuroimmune processes in a sex-dependent manner, particularly within the hippocampus. Coumestrol, a plant estrogen, is promoted as an alternative to post-menopausal hormone therapy due to its various mechanisms that enhance brain health, including its anti-inflammatory effects. This study aimed to investigate whether coumestrol pretreatment could attenuate the neuroinflammatory response following CGI by regulating pro-inflammatory pathways (GFAP, S100B, TNF-α, and IL-1β) and reversing CGI-induced memory loss.

Male and female rats underwent CGI for 10 min or a sham surgery and received an ICV infusion of 20 μg of coumestrol or vehicle 1 h before CGI induction. Our findings revealed intriguing sex-specific effects of coumestrol pretreatment on gliosis following CGI and reperfusion, suggesting modulation of glial responses after ischemic insults. Coumestrol pre-administration significantly reduced levels of pro-inflammatory cytokines TNF-α and IL-1β during both reperfusion periods in both sexes, thereby mitigating CGI-induced neuroinflammation. Moreover, coumestrol pretreatment effectively reduced stroke-induced cognitive impairment, alleviating ischemia-induced memory deficits in both male and female rats. These results demonstrate the coumestrol's ability to attenuate cognitive deficits induced by CGI and highlight its potential sex-specific effects on inflammatory pathways. This study suggests that coumestrol modulates the glial and microglial inflammatory response, offering a promising approach to mitigate memory deficits associated with cerebral global ischemia.

脑缺血（CGI）是一种破坏性的神经系统疾病，每年影响全球数百万人，导致严重的炎症反应和长期后果，包括延迟的神经元死亡和神经认知障碍。脑损伤后，驻留的小胶质细胞被激活，触发促炎细胞因子的表达，并以性别依赖的方式改变神经免疫过程，特别是在海马体中。库美孕是一种植物雌激素，由于其多种机制可以增强大脑健康，包括其抗炎作用，因此被推广为绝经后激素治疗的替代方案。本研究旨在探讨库美特罗预处理是否可以通过调节促炎通路（GFAP、S100B、TNF-α和IL-1β）和逆转CGI诱导的记忆丧失来减轻CGI后的神经炎症反应。雄性和雌性大鼠进行CGI诱导10 min或假手术，并在CGI诱导前1 h接受ICV注射20 μg的库米司醇或对照物。我们的研究结果揭示了库美特罗预处理对CGI和再灌注后胶质细胞形成的有趣的性别特异性作用，提示缺血损伤后胶质细胞反应的调节。在再灌注期间，给药前库美特罗显著降低了两性的促炎细胞因子TNF-α和IL-1β水平，从而减轻了cgi诱导的神经炎症。此外，在雄性和雌性大鼠中，库美特罗预处理有效地减少了脑卒中引起的认知障碍，减轻了缺血引起的记忆缺陷。这些结果表明，库美特罗有能力减轻CGI引起的认知缺陷，并强调其对炎症途径的潜在性别特异性影响。本研究表明，库美特罗可调节神经胶质细胞和小神经胶质细胞的炎症反应，为减轻与脑缺血相关的记忆缺陷提供了一种有希望的方法。

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引用次数: 0

Microglia-like cells from patient monocytes demonstrate increased phagocytic activity in probable Alzheimer's disease 来自患者单核细胞的小胶质样细胞在可能的阿尔茨海默病中显示出增加的吞噬活性。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2024-12-27 DOI: 10.1016/j.mcn.2024.103990

Ceren Perihan Gonul , Cagla Kiser , Emis Cansu Yaka , Didem Oz , Duygu Hunerli , Deniz Yerlikaya , Melis Olcum , Pembe Keskinoglu , Gorsev Yener , Sermin Genc

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by the accumulation of amyloid plaques, phosphorylated tau tangles and microglia toxicity, resulting in neuronal death and cognitive decline. Since microglia are recognized as one of the key players in the disease, it is crucial to understand how microglia operate in disease conditions and incorporate them into models. The studies on human microglia functions are thought to reflect the post-symptomatic stage of the disease. Recently developed methods involve induced microglia-like cells (iMGs) generated from patients' blood monocytes or induced pluripotent stem cells (iPSCs) as an alternative to studying the microglia cells in vitro. In this research, we aimed to investigate the phenotype and inflammatory responses of iMGs from AD patients. Monocytes derived from blood using density gradient centrifugation were differentiated into iMGs using a cytokine cocktail, including granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-34 (IL-34). After differentiation, cells were assessed by morphological analysis and a microglia surface marker, TMEM119. We used stimulants, lipopolysaccharide (LPS) and beta-amyloid, to examine iMGs' functions. Results showed that iMGs derived from AD patients exhibited increased secretion of pro-inflammatory cytokines upon LPS stimulation. Furthermore, their phagocytic ability was also heightened in stimulated and unstimulated conditions, with cells derived from patients showing increased phagocytic activity compared to healthy controls. Overall, these findings suggest that iMGs derived from patients using the direct conversion method possess characteristics of human microglia, making them an easy and promising model for studying microglia function in AD.

阿尔茨海默病（AD）是一种神经退行性疾病，其特征是淀粉样斑块积累、磷酸化tau缠结和小胶质细胞毒性，导致神经元死亡和认知能力下降。由于小胶质细胞被认为是疾病的关键参与者之一，因此了解小胶质细胞在疾病条件下如何运作并将其纳入模型至关重要。对人类小胶质细胞功能的研究被认为反映了该疾病的症状后阶段。最近发展的方法涉及从患者血液单核细胞或诱导多能干细胞（iPSCs）中产生的诱导小胶质细胞样细胞（iMGs）作为体外研究小胶质细胞的替代方法。在本研究中，我们旨在研究AD患者iMGs的表型和炎症反应。采用密度梯度离心从血液中提取的单核细胞通过细胞因子混合物（包括粒细胞-巨噬细胞集落刺激因子（GM-CSF）和白细胞介素-34 (IL-34)）分化为iMGs。分化后，通过形态学分析和小胶质细胞表面标记物TMEM119来评估细胞。我们使用兴奋剂、脂多糖（LPS）和β -淀粉样蛋白来检测iMGs的功能。结果表明，来自AD患者的img在LPS刺激下显示出促炎细胞因子的分泌增加。此外，他们的吞噬能力也在刺激和非刺激条件下增强，与健康对照相比，来自患者的细胞显示出更高的吞噬活性。总的来说，这些发现表明，使用直接转换方法获得的患者img具有人类小胶质细胞的特征，使其成为研究AD小胶质细胞功能的简单且有希望的模型。

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引用次数: 0

Glutathione S-transferase: A keystone in Parkinson's disease pathogenesis and therapy 谷胱甘肽s -转移酶：帕金森病发病机制和治疗的关键。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2024-12-05 DOI: 10.1016/j.mcn.2024.103981

Pratyush Padhan , Simran , Neeraj Kumar , Sonia Verma

Parkinson's disease is a progressive neurodegenerative disorder that predominantly affects motor function due to the loss of dopaminergic neurons in the substantia nigra. It presents significant challenges, impacting millions worldwide with symptoms such as tremors, rigidity, bradykinesia, and postural instability, leading to decreased quality of life and increased morbidity. The pathogenesis of Parkinson's disease is multifaceted, involving complex interactions between genetic susceptibility, environmental factors, and aging, with oxidative stress playing a central role in neuronal degeneration. Glutathione S-Transferase enzymes are critical in the cellular defense mechanism against oxidative stress, catalysing the conjugation of the antioxidant glutathione to various toxic compounds, thereby facilitating their detoxification. Recent research underscores the importance of Glutathione S-Transferase in the pathophysiology of Parkinson's disease, revealing that genetic polymorphisms in Glutathione S-Transferase genes influence the risk and progression of the disease. These genetic variations can affect the enzymatic activity of Glutathione S-Transferase, thereby modulating an individual's capacity to detoxify reactive oxygen species and xenobiotics, which are implicated in Parkinson's disease neuropathological processes. Moreover, biochemical studies have elucidated the role of Glutathione S-Transferase in not only maintaining cellular redox balance but also in modulating various cellular signalling pathways, highlighting its neuroprotective potential. From a therapeutic perspective, targeting Glutathione S-Transferase pathways offers promising avenues for the development of novel treatments aimed at enhancing neuroprotection and mitigating disease progression. This review explores the evident and hypothesized roles of Glutathione S-Transferase in Parkinson's disease, providing a comprehensive overview of its importance and potential as a target for therapeutic intervention.

帕金森病是一种进行性神经退行性疾病，主要由于黑质多巴胺能神经元的丧失而影响运动功能。它带来了重大挑战，影响了全世界数百万人的症状，如震颤、僵硬、运动迟缓和姿势不稳，导致生活质量下降和发病率增加。帕金森病的发病机制是多方面的，涉及遗传易感性、环境因素和衰老之间复杂的相互作用，氧化应激在神经元变性中起核心作用。谷胱甘肽s -转移酶在细胞防御氧化应激机制中起着至关重要的作用，它催化抗氧化剂谷胱甘肽与各种有毒化合物结合，从而促进它们的解毒。最近的研究强调了谷胱甘肽s -转移酶在帕金森病病理生理中的重要性，揭示了谷胱甘肽s -转移酶基因的遗传多态性影响疾病的风险和进展。这些遗传变异可以影响谷胱甘肽s -转移酶的酶活性，从而调节个体对活性氧和异种生物解毒的能力，这与帕金森病的神经病理过程有关。此外，生物化学研究已经阐明了谷胱甘肽s -转移酶不仅在维持细胞氧化还原平衡中发挥作用，而且在调节各种细胞信号通路中发挥作用，突出了其神经保护潜力。从治疗的角度来看，靶向谷胱甘肽s -转移酶途径为开发旨在增强神经保护和缓解疾病进展的新疗法提供了有希望的途径。这篇综述探讨了谷胱甘肽s -转移酶在帕金森病中明显的和假设的作用，全面概述了其作为治疗干预靶点的重要性和潜力。

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引用次数: 0

Microfluidics in neural extracellular vesicles characterization for early Alzheimer's disease diagnosis 神经细胞外囊泡的微流体特征在早期阿尔茨海默病诊断中的应用。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2024-12-03 DOI: 10.1016/j.mcn.2024.103982

Hossein Zare , Michelle M. Kasdorf , Amirala Bakhshian Nik

Dementia is a general term for conditions impairing cognitive abilities including perception, reasoning, attention, judgment, memory, and daily brain function. Early diagnosis of Alzheimer's disease (AD), the most common form of dementia, using neural extracellular vesicles (nEVs) is the focus of the current study. These nEVs carry AD biomarkers including β-amyloid proteins and phosphorylated tau proteins. The novelty of this review lies in developing a microfluidic perspective by introducing the techniques using a microfluidic platform for early diagnosis of AD. A microfluidic device can detect small sample sizes with significantly low concentrations. These devices combine nEV isolation, enrichment, and detection, which makes them ideal candidates for early AD diagnosis.

痴呆症是认知能力受损的总称，包括感知、推理、注意力、判断、记忆和日常大脑功能。利用神经细胞外囊泡（nev）对阿尔茨海默病（AD）的早期诊断是当前研究的重点。这些nev携带AD生物标志物，包括β-淀粉样蛋白和磷酸化的tau蛋白。本文的新颖之处在于从微流控的角度介绍了利用微流控平台进行AD早期诊断的技术。微流控装置可以检测低浓度的小样本。这些设备结合了新能源病毒的分离、富集和检测，使其成为早期AD诊断的理想候选设备。

引用次数: 0

The mRNA expression profile of glycine receptor subunits alpha 1, alpha 2, alpha 4 and beta in female and male mice 雌性和雄性小鼠甘氨酸受体亚基 alpha 1、alpha 2、alpha 4 和 beta 的 mRNA 表达谱。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2024-12-01 DOI: 10.1016/j.mcn.2024.103976

Mikaela M. Ceder, Kajsa A. Magnusson, Hannah M. Weman, Katharina Henriksson, Linn Andréasson, Teresa Lindström, Oskar Wiggins, Malin C. Lagerström

Glycine receptors are ligand-gated chloride-selective channels that control excitability in the central nervous system (CNS). Herein, we have investigated the mRNA expression of the glycine receptor alpha 1 (Glra1), alpha 2 (Glra2), alpha 4 (Glra4) and the beta (Glrb) subunits, in adult female and male mice.

Single-cell RNA sequencing data re-analysis of the Zeisel et al. (2018) dataset indicated widespread expression of Glra1, Glra2 and Glrb in the CNS, while only a few cells in the cortex, striatum, thalamus, midbrain and the spinal cord expressed Glra4. Highest occurrence of Glra1, Glra2 and Glrb were found in the brainstem. Moreover, Glra1 and Glrb were revealed to have the highest occurrences in the spinal cord of the investigated subunits. However, both Glra2 and Glrb had a more widespread expression in the CNS compared with Glra1 and Glra4. Bulk quantitative real-time-PCR (qRT-PCR) analysis revealed Glra1 expression in the hypothalamus, thalamus, brainstem and the spinal cord, and widespread, but low, Glra2 and Glrb expression in the CNS. Moreover, Glrb could be detected in a few visceral organs. Additionally, females and males were found to express Glra1, Glra2 and Glrb differently in certain brain areas such as the brainstem. Expression levels of Glra4 were too low to be detected using qRT-PCR. Lastly, RNAscope spatially validated the expression of Glra1, Glra2 and Glrb in the areas indicated by the single-cell and bulk analyses, and further revealed that Glra4 can be detected in the cortex, amygdala, hypothalamus, thalamus, brainstem, especially the cochlear nucleus, and in the spinal cord.

甘氨酸受体是配体门控的氯离子选择性通道，可控制中枢神经系统（CNS）的兴奋性。在此，我们研究了成年雌性和雄性小鼠甘氨酸受体α1（Glra1）、α2（Glra2）、α4（Glra4）和β（Glrb）亚基的 mRNA 表达。对Zeisel等人（2018年）数据集进行的单细胞RNA测序数据再分析表明，Glra1、Glra2和Glrb在中枢神经系统中广泛表达，而皮层、纹状体、丘脑、中脑和脊髓中只有少数细胞表达Glra4。Glra1、Glra2和Glrb在脑干的出现率最高。此外，在所研究的亚单位中，Glra1 和 Glrb 在脊髓中的出现率最高。不过，与 Glra1 和 Glra4 相比，Glra2 和 Glrb 在中枢神经系统中的表达更为广泛。大量实时定量 PCR（qRT-PCR）分析显示，Glra1 在下丘脑、丘脑、脑干和脊髓中表达，Glra2 和 Glrb 在中枢神经系统中广泛表达，但表达量较低。此外，在一些内脏器官中也能检测到 Glrb。此外，还发现雌性和雄性在某些脑区（如脑干）的Glra1、Glra2和Glrb表达量不同。Glra4 的表达水平太低，无法通过 qRT-PCR 检测到。最后，RNAscope 从空间上验证了 Glra1、Glra2 和 Glrb 在单细胞和大块分析所显示区域的表达，并进一步发现在大脑皮层、杏仁核、下丘脑、丘脑、脑干（尤其是耳蜗核）和脊髓中可以检测到 Glra4。

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引用次数: 0

Potential key pathophysiological participant and treatment target in autism spectrum disorder: Microglia 自闭症谱系障碍的潜在关键病理生理参与者和治疗目标：小胶质细胞

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2024-11-22 DOI: 10.1016/j.mcn.2024.103980

Zehua Tan , Ruixin Xia , Xin Zhao , Zile Yang, Haiying Liu, Wenting Wang

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by social and communication deficits, as well as restricted or repetitive behaviors or interests. Although the etiology of ASD remains unclear, there is abundant evidence suggesting that microglial dysfunction is likely to be a significant factor in the pathophysiology of ASD. Microglia, the primary innate immune cells in the central nervous system (CNS), play a crucial role in brain development and homeostasis. Recently, numerous studies have shown that microglia in ASD models display various abnormalities including morphology, function, cellular interactions, genetic and epigenetic factors, as well as the expression of receptors, transcription factors, and cytokines. They impact normal neural development through various mechanisms contributing to ASD, such as neuroinflammation, and alterations in synaptic formation and pruning. The focus of this review is on recent studies regarding microglial abnormalities in ASD and their effects on the onset and progression of ASD at both cellular and molecular levels. It can provide insight into the specific contribution of microglia to ASD pathogenesis and help in designing potential therapeutic and preventative strategies targeting microglia.

自闭症谱系障碍（ASD）是一组神经发育障碍，其特点是社交和沟通障碍，以及行为或兴趣受限或重复。虽然自闭症谱系障碍的病因尚不清楚，但有大量证据表明，小胶质细胞功能障碍可能是自闭症谱系障碍病理生理学中的一个重要因素。小胶质细胞是中枢神经系统（CNS）的主要先天性免疫细胞，在大脑发育和平衡中发挥着至关重要的作用。最近，大量研究表明，ASD 模型中的小胶质细胞表现出各种异常，包括形态、功能、细胞相互作用、遗传和表观遗传因素，以及受体、转录因子和细胞因子的表达。它们通过导致 ASD 的各种机制影响正常的神经发育，如神经炎症、突触形成和修剪的改变。本综述的重点是有关 ASD 中小胶质细胞异常及其在细胞和分子水平上对 ASD 发病和进展的影响的最新研究。它有助于深入了解小胶质细胞对 ASD 发病机制的具体作用，并有助于设计针对小胶质细胞的潜在治疗和预防策略。

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引用次数: 0

Sphingosine-1-phosphate receptor 3 promotes neuronal apoptosis via the TNF-α/caspase-3 signaling pathway after acute intracerebral hemorrhage 急性脑内出血后，鞘磷脂-1-磷酸受体 3 通过 TNF-α/caspase-3 信号通路促进神经细胞凋亡

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2024-11-22 DOI: 10.1016/j.mcn.2024.103979

Dengpan Song , Mengyuan Li , Longxiao Zhang , Kaiyuan Zhang , Yuan An , Mengzhao Feng , Fang Wang , Chi-Tai Yeh , Jian Wang , Fuyou Guo

Background

Intracerebral hemorrhage (ICH) has a high incidence and mortality rate among cerebrovascular diseases, and effective treatments are lacking. Sphingosine-1-phosphate receptor 3 (S1PR3) is associated with secondary immune inflammatory injury following ICH. However, its relationship with neuronal apoptosis and the specific underlying mechanism are not clear.

Methods

We observed the effect of S1PR3 on neuronal apoptosis by assessing neurobehavioral scores, performing Western blot (WB) analysis, and performing TUNEL staining in a mouse model of ICH. Moreover, WBs and flow cytometry were used to study the specific mechanism and signaling pathways in HT22 cells in vitro.

Results

The expression of S1PR3, CCL2, TNF-α, and cleaved-caspase-3 (c-caspase-3) and neuronal apoptosis were significantly increased after ICH, accompanied by neurobehavioral deterioration. These effects were significantly improved by treatment with CAY10444, a specific S1PR3 antagonist. After S1P stimulation of HT22 cells, the expression of S1PR3, CCL2, TNF-α and c-caspase-3 increased, and neuronal apoptosis increased by activating caspase-3 through the downstream PI3K/AKT apoptosis signaling pathway. After CAY10444 treatment, the expression of CCL2, TNF-α and c-caspase-3 was significantly reduced, and the PI3K/AKT apoptotic signaling pathway was regulated to reduce neuronal apoptosis.

Conclusion

An increase in S1P/S1PR3 after ICH may induce neuronal apoptosis by increasing TNF-α expression and activating the PI3K/AKT signaling pathway and the expression of caspase-3 effector proteins. CAY10444 can reduce neuronal apoptosis, improve symptoms and play a neuroprotective role by antagonizing S1PR3. S1PR3 may be a promising therapeutic target.

背景在脑血管疾病中，脑出血（ICH）的发病率和死亡率都很高，而且缺乏有效的治疗方法。两性鞘氨醇-1-磷酸受体 3（S1PR3）与 ICH 后的继发性免疫炎症损伤有关。我们在 ICH 小鼠模型中通过神经行为评分、Western 印迹（WB）分析和 TUNEL 染色观察了 S1PR3 对神经细胞凋亡的影响。结果 ICH后S1PR3、CCL2、TNF-α和裂解-caspase-3（c-caspase-3）的表达和神经元凋亡显著增加，并伴随神经行为的恶化。使用特异性 S1PR3 拮抗剂 CAY10444 治疗可明显改善这些影响。S1P刺激HT22细胞后，S1PR3、CCL2、TNF-α和c-caspase-3的表达增加，通过下游的PI3K/AKT凋亡信号通路激活caspase-3，从而增加神经元凋亡。CAY10444治疗后，CCL2、TNF-α和c-caspase-3的表达明显减少，PI3K/AKT凋亡信号通路被调控，从而减少神经元凋亡。CAY10444 可通过拮抗 S1PR3 减少神经元凋亡，改善症状，发挥神经保护作用。S1PR3 可能是一个很有前景的治疗靶点。

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引用次数: 0

TAT-PPA1 protects against oxidative stress-induced loss of dopaminergic neurons TAT-PPA1 可防止氧化应激诱导的多巴胺能神经元丧失。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2024-10-31 DOI: 10.1016/j.mcn.2024.103978

Hyun Jung Kwon , Hyo Young Jung , Soo Young Choi , In Koo Hwang , Dae Won Kim , Min Jea Shin

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) of the midbrain, resulting in severe motor impairments. Inorganic pyrophosphatase 1 (PPA1) plays a key role in various biological processes, and this study introduces a cell-penetrating PPA1 fusion protein (TAT-PPA1) to explore its transduction into cells and brain tissues. TAT-PPA1 effectively penetrates SH-SY5Y cells and the SN region of PD animal models without toxicity, exhibiting protective effects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-)-induced cell death. TAT-PPA1 revealed an inhibitory influence on the MAPK signaling pathway and MPTP-induced reactive oxygen species (ROS) production. TAT-PPA1 suppresses JNK, AKT, p53, ERK, and p38 phosphorylation, showcasing its multifaceted role in cell survival pathways. In the MPTP-induced PD animal model, TAT-PPA1 prevents dopaminergic cell death and enhances motor function. This study shows that TAT-PPA1 protects against oxidative stress and cell death in neurodegenerative diseases, suggesting potential as a PD treatment.

帕金森病（Parkinson's disease，PD）是一种神经退行性疾病，以中脑黑质（substantia nigra，SN）多巴胺能神经元的进行性丧失为特征，导致严重的运动障碍。无机焦磷酸酶1（PPA1）在多种生物过程中发挥着关键作用，本研究引入了一种细胞穿透性PPA1融合蛋白（TAT-PPA1），以探索其在细胞和脑组织中的转导。TAT-PPA1能有效穿透SH-SY5Y细胞和PD动物模型的SN区域，且无毒性，对1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的细胞死亡有保护作用。TAT-PPA1 对 MAPK 信号通路和 MPTP 诱导的活性氧（ROS）产生有抑制作用。TAT-PPA1 可抑制 JNK、AKT、p53、ERK 和 p38 的磷酸化，显示了它在细胞存活通路中的多方面作用。在 MPTP 诱导的帕金森病动物模型中，TAT-PPA1 可防止多巴胺能细胞死亡并增强运动功能。这项研究表明，TAT-PPA1 可防止神经退行性疾病中的氧化应激和细胞死亡，具有治疗帕金森病的潜力。

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引用次数: 0

Inhibition of phosphodiesterase 10A mitigates neuronal injury by modulating apoptotic pathways in cold-induced traumatic brain injury 抑制磷酸二酯酶10A可通过调节冷诱导的创伤性脑损伤中的细胞凋亡途径减轻神经元损伤。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2024-10-20 DOI: 10.1016/j.mcn.2024.103977

Mustafa C. Beker , Mehmet O. Altintas , Enes Dogan , Cigdem Bayraktaroglu , Buse Balaban , Aysenur Ozpinar , Nursena Sengun , Serdar Altunay , Ertugrul Kilic

Brain injury develops from a complex series of pathophysiological phases, resulting in acute necrotic or delayed apoptotic cell death after traumatic brain injury (TBI). Inhibition of apoptotic cell death is critical for the treatment of acute neurodegenerative disorders, such as TBI. Here, we investigated the role of phosphodiesterase 10A (PDE10A) in the development of neuronal injury, particularly in apoptotic cell death. Using the PDE10A inhibitor TAK-063, we found that PDE10A inhibition is associated with decreased brain injury, brain swelling, and blood brain barrier disruption 48 h after cold-induced TBI. Furthermore, a particularly notable result was observed with 3 mg/kg TAK-063, which reduced disseminated neuronal injury. Protein abundance analysis revealed that PDE10A inhibition activates survival kinases AKT and ERK-1/-2, which were associated with the decreased activation of MMP-9 and PTEN. Additionally, iNOS and nNOS levels significantly reduced in the TAK-063 group, playing roles in inflammation and apoptosis. A planar surface immunoassay was performed for in-depth analyses of the apoptotic signaling pathways. We observed that inhibition of PDE10A resulted in the decreased expression of TNFRSF1A, TNFRSF10B, and TNFRSF6 receptors, particularly inducing apoptotic cell death. Moreover, these findings correlated with reduced levels of pro-apoptotic proteins, including PTEN, p27, Cytochrome-c, cleaved Caspase-3, Bad, and p53. Interestingly, TAK-063 treatment reduced levels of anti-apoptotic proteins or enzymes, including XIAP, Claspin, and HIF1α, without affecting Bcl-x, MCL-1, SMAC, HO-1, HO-2, HSP27, HSP60, and HSP70. The findings suggest that PDE10A regulates cellular signaling predominantly pro-apoptotic pathways, and inhibition of this protein is a promising approach for the treatment of acute brain injury.

脑损伤是由一系列复杂的病理生理阶段发展而来的，导致创伤性脑损伤（TBI）后细胞急性坏死或延迟凋亡。抑制细胞凋亡对于治疗创伤性脑损伤等急性神经退行性疾病至关重要。在这里，我们研究了磷酸二酯酶 10A（PDE10A）在神经元损伤的发展过程中，尤其是在细胞凋亡中的作用。通过使用 PDE10A 抑制剂 TAK-063，我们发现 PDE10A 抑制与冷诱导创伤性脑损伤 48 小时后脑损伤、脑肿胀和血脑屏障破坏的减少有关。此外，3 毫克/千克的 TAK-063 还能减少弥散性神经元损伤，效果尤为显著。蛋白质丰度分析表明，PDE10A 抑制可激活存活激酶 AKT 和 ERK-1/-2，这与 MMP-9 和 PTEN 的激活减少有关。此外，TAK-063 组的 iNOS 和 nNOS 水平明显降低，它们在炎症和细胞凋亡中发挥作用。为了深入分析细胞凋亡信号通路，我们进行了平面表面免疫测定。我们观察到，抑制 PDE10A 会导致 TNFRSF1A、TNFRSF10B 和 TNFRSF6 受体的表达减少，尤其会诱导细胞凋亡。此外，这些发现与促凋亡蛋白水平的降低有关，包括 PTEN、p27、细胞色素-c、裂解的 Caspase-3、Bad 和 p53。有趣的是，TAK-063 处理降低了抗凋亡蛋白或酶的水平，包括 XIAP、Claspin 和 HIF1α，但不影响 Bcl-x、MCL-1、SMAC、HO-1、HO-2、HSP27、HSP60 和 HSP70。研究结果表明，PDE10A主要调节细胞信号传导的促凋亡通路，抑制该蛋白是治疗急性脑损伤的一种很有前景的方法。

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引用次数: 0

Vulnerability of neurofilament-expressing neurons in frontotemporal dementia 额颞叶痴呆症中神经丝表达神经元的脆弱性。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2024-10-05 DOI: 10.1016/j.mcn.2024.103974

Nina Daniels, Aidan D. Bindoff, James C. Vickers, Anna E. King , Jessica M. Collins

Frontotemporal dementia (FTD) is an umbrella term for several early onset dementias, that are caused by frontotemporal lobar degeneration (FTLD), which involves the atrophy of the frontal and temporal lobes of the brain. Neuron loss in the frontal and temporal lobes is a characteristic feature of FTLD, however the selective vulnerability of different neuronal populations in this group of diseases is not fully understood. Neurofilament-expressing neurons have been shown to be selectively vulnerable in other neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, therefore we sought to investigate whether this neuronal population is vulnerable in FTLD. We also examined whether neuronal sub-type vulnerability differed between FTLD with TDP-43 inclusions (FTLD-TDP) and FTLD with tau inclusions (FTLD-Tau). Post-mortem human tissue from the superior frontal gyrus (SFG) of FTLD-TDP (n = 15), FTLD-Tau (n = 8) and aged Control cases (n = 6) was immunolabelled using antibodies against non-phosphorylated neurofilaments (SMI32 antibody), calretinin and NeuN, to explore neuronal cell loss. The presence of non-phosphorylated neurofilament immunolabelling in axons of the SFG white matter was also quantified as a measure of axon pathology, as axonal neurofilaments are normally phosphorylated. We demonstrate the selective loss of neurofilament-expressing neurons in both FTLD-TDP and FTLD-Tau cases compared to aged Controls. We also show that non-phosphorylated neurofilament axonal pathology in the SFG white matter was associated with increasing age, but not FTLD. This data suggests neurofilament-expressing neurons are vulnerable in both FTLD-TDP and FTLD-Tau.

额颞叶痴呆症（FTD）是多种早发性痴呆症的总称，由额颞叶变性（FTLD）引起，涉及大脑额叶和颞叶的萎缩。额叶和颞叶的神经元缺失是额颞叶变性的一个特征，但这组疾病中不同神经元群的选择性易感性尚不完全清楚。在其他神经退行性疾病（包括阿尔茨海默病和肌萎缩侧索硬化症）中，神经丝表达的神经元已被证明具有选择性易损性，因此我们试图研究这一神经元群在 FTLD 中是否易损。我们还研究了带有 TDP-43 包涵体的 FTLD（FTLD-TDP）和带有 tau 包涵体的 FTLD（FTLD-Tau）之间神经元亚型的易损性是否存在差异。使用针对非磷酸化神经丝（SMI32 抗体）、钙视蛋白和 NeuN 的抗体对 FTLD-TDP（n = 15）、FTLD-Tau（n = 8）和老年对照病例（n = 6）的额叶上回（SFG）死后人体组织进行免疫标记，以检测神经细胞丢失情况。由于轴突神经丝通常是磷酸化的，因此还对 SFG 白质轴突中存在的非磷酸化神经丝免疫标记进行了量化，作为衡量轴突病理学的一个指标。我们发现，与老年对照组相比，FTLD-TDP 和 FTLD-Tau 病例中神经丝表达神经元的选择性缺失。我们还发现，SFG 白质中的非磷酸化神经丝轴突病变与年龄增长有关，但与 FTLD 无关。这些数据表明，表达神经丝的神经元在FTLD-TDP和FTLD-Tau中都很脆弱。

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引用次数: 0