Dual action of sphingosine 1-phosphate pathway in in vitro models of global cerebral ischemia

1-磷酸鞘氨醇通路在全脑缺血体外模型中的双重作用

It is well accepted that sphingolipids play an important role in the pathological process of cerebral ischemia. In the present study we have investigated the involvement of sphingosine 1-phosphate (S1P) pathway in two different in vitro models of global ischemia. In organotypic hippocampal slices exposed to oxygen and glucose deprivation (OGD) we evaluated the mRNA expression of S1P metabolic enzymes and receptors (S1P1-5) by Real Time-PCR. In the same model we investigated the effect of the inhibitor of S1P lyase (SPL), LX2931, the selective antagonists of S1P2, JTE-013, and S1P3, CAY10444, quantifying the cell death in the CA1 region by propidium iodide fluorescence, and morphological and tissue organization alterations by immunohistochemistry and confocal microscopy. Moreover, we performed extracellular recordings of field excitatory postsynaptic potentials in acute slices exposed to OGD. In organotypic slices OGD induced a significant increase of SPL at mRNA level and of S1P2 and S1P3 at both mRNA and protein level. The incubation with LX2931, JTE-013 or CAY10444 was able to reduce CA1 damage induced by OGD in organotypic slices and provoked a significant delay of the onset of anoxic depolarization on acute slices. Moreover, S1P2 and S1P3 antagonists prevented the increase of TREM2 induced by OGD. Our results reveal a dual role of S1P pathway in brain ischemia: intracellular S1P, degraded via SPL, appears to be beneficial whereas signaling via S1P2 and S1P3 is detrimental to the disease. These findings support the notion that SPL, S1P2 and S1P3 are promising therapeutic targets in brain ischemia.

人们普遍认为，鞘脂类在脑缺血的病理过程中起着重要作用。在本研究中，我们探究了鞘氨醇-1-磷酸（S1P）通路在两种不同的全脑缺血体外模型中的作用。在暴露于氧糖剥夺（OGD）的器官型海马切片中，我们通过实时聚合酶链反应评估了S1P代谢酶和受体（S1P1 - 5）的mRNA表达。在同一模型中，我们研究了S1P裂解酶（SPL）抑制剂LX2931、S1P2选择性拮抗剂JTE - 013和S1P3选择性拮抗剂CAY10444的作用，通过碘化丙啶荧光定量CA1区的细胞死亡情况，并通过免疫组织化学和共聚焦显微镜观察形态和组织结构的改变。此外，我们对暴露于OGD的急性切片进行了场兴奋性突触后电位的细胞外记录。在器官型切片中，OGD诱导SPL的mRNA水平显著升高，S1P2和S1P3的mRNA和蛋白水平均显著升高。用LX2931、JTE - 013或CAY10444孵育能够减少OGD在器官型切片中诱导的CA1区损伤，并使急性切片中缺氧去极化的起始时间显著延迟。此外，S1P2和S1P3拮抗剂可防止OGD诱导的TREM2升高。我们的研究结果揭示了S1P通路在脑缺血中的双重作用：通过SPL降解的细胞内S1P似乎有益，而通过S1P2和S1P3的信号传导对疾病有害。这些发现支持了SPL、S1P2和S1P3是脑缺血有前景的治疗靶点这一观点。

REF: Mazzantini C, Venturini M, Lana D, et al. Dual action of sphingosine 1-phosphate pathway in in vitro models of global cerebral ischemia. Neurobiol Dis. 2025;208:106865. doi:10.1016/j.nbd.2025.106865 PMID: 40068722

Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration

线粒体处于十字路口：神经元衰老和神经退行性变中的质量控制机制

Mitochondria play a central role in essential cellular processes, including energy metabolism, biosynthesis of metabolic substances, calcium ion storage, and regulation of cell death. Maintaining mitochondrial quality control is critical for preserving mitochondrial health and ensuring cellular function. Given their high energy demands, neurons depend on effective mitochondrial quality control to sustain their health and functionality. Neuronal senescence, characterized by a progressive decline in structural integrity and function, is a hallmark of neurodegenerative diseases. In senescent neurons, abnormal mitochondrial morphology, functional impairments, increased reactive oxygen species production and disrupted quality control mechanisms are frequently observed. Understanding the pathological changes in neuronal structure, exploring the intricate relationship between mitochondrial quality control and neuronal health, and leveraging mitochondrial quality control interventions provide a promising foundation for addressing age-related neurodegenerative diseases. This review highlights key mitochondrial quality control, including biogenesis, dynamics, the ubiquitin-proteasome system, autophagy pathways, mitochondria-derived vesicles, and inter-organelle communication, while discussing their roles in neuronal senescence and potential therapeutic strategies. These insights may pave the way for innovative treatments to mitigate neurodegenerative disorders.

线粒体在重要的细胞过程中起着核心作用，包括能量代谢、代谢物质的生物合成、钙离子储存以及细胞死亡的调控。维持线粒体质量控制对于保持线粒体健康和确保细胞功能至关重要。由于神经元对能量的需求极高，它们依赖有效的线粒体质量控制来维持自身的健康和功能。神经元衰老以结构完整性和功能的渐进性衰退为特征，是神经退行性疾病的一个标志。在衰老的神经元中，经常会观察到线粒体形态异常、功能受损、活性氧生成增加以及质量控制机制紊乱等情况。了解神经元结构的病理变化，探索线粒体质量控制与神经元健康之间的复杂关系，并利用线粒体质量控制干预措施，为解决与年龄相关的神经退行性疾病提供了一个有前景的基础。这篇综述重点介绍了关键的线粒体质量控制机制，包括生物发生、动力学、泛素 - 蛋白酶体系统、自噬途径、线粒体衍生囊泡以及细胞器间的通讯，同时讨论了它们在神经元衰老中的作用以及潜在的治疗策略。这些见解可能为缓解神经退行性疾病的创新疗法铺平道路。

REF: Zheng Y, Yang J, Li X, et al. Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration. Neurobiol Dis. 2025;208:106862. doi:10.1016/j.nbd.2025.106862 PMID: 40049539

Towards a better diagnosis and treatment of dementia: Identifying common and distinct neuropathological mechanisms in Alzheimer's and vascular dementia

迈向痴呆症更好的诊断与治疗：识别阿尔茨海默病和血管性痴呆常见及独特的神经病理机制

Alzheimer's disease (AD) and vascular dementia (VaD) together contribute to almost 90 % of all dementia cases leading to major health challenges of our time with a substantial global socioeconomic burden. While in AD, the improved understanding of Amyloid beta (Aß) mismetabolism and tau hyperphosphorylation as pathophysiological hallmarks has led to significant clinical breakthroughs, similar advances in VaD are lacking. After comparing the clinical presentation, including risk factors, disease patterns, course of diseases and further diagnostic parameters for both forms of dementia, we highlight the importance of shared pathomechanisms found in AD and VaD: Endothelial damage, blood brain barrier (BBB) breakdown and hypoperfusion inducing oxidative stress and inflammation and thus trophic uncoupling in the neurovascular unit. A dysfunctional endothelium and BBB lead to the accumulation of neurotoxic molecules and Aß through impaired clearance, which in turn leads to neurodegeneration. In this context we discuss possible neuropathological parameters, which might serve as biomarkers and thus improve diagnostic accuracy or reveal targets for novel therapeutic strategies for both forms of dementia.

阿尔茨海默病（AD）和血管性痴呆（VaD）共同构成了近90%的痴呆病例，给当今社会带来了重大的健康挑战，并造成了巨大的全球社会经济负担。在AD中，对淀粉样蛋白β（Aß）代谢异常和tau蛋白过度磷酸化这两个病理生理学特征的深入了解已带来了重大的临床突破，但VaD在这方面却缺乏类似进展。在比较了这两种痴呆的临床表现，包括危险因素、疾病模式、病程以及其他诊断参数后，我们强调了AD和VaD共同存在的病理机制的重要性：内皮损伤、血脑屏障（BBB）破坏和低灌注引发氧化应激和炎症，进而导致神经血管单元的营养耦合失调。功能失调的内皮细胞和血脑屏障会因清除功能受损而导致神经毒性分子和Aß积累，进而引发神经退行性病变。在此背景下，我们探讨了可能的神经病理学参数，这些参数或许可作为生物标志物，从而提高诊断准确性，或为这两种痴呆的新型治疗策略揭示靶点。

REF: Vollhardt A, Frölich L, Stockbauer AC, Danek A, Schmitz C, Wahl AS. Towards a better diagnosis and treatment of dementia: Identifying common and distinct neuropathological mechanisms in Alzheimer's and vascular dementia. Neurobiol Dis. 2025;208:106845. doi:10.1016/j.nbd.2025.106845 PMID: 39999928

Leveraging animal models to understand non-motor symptoms of Parkinson's disease

利用动物模型来了解帕金森病的非运动症状

Parkinson's disease is diagnosed based on motor symptoms, but non-motor symptoms of the disease, such as cognitive impairment, autonomic dysfunction, hyposmia, sleep disorders, and psychiatric disorders heavily impact patient and caregiver quality of life. It has proven challenging to faithfully reproduce and quantify these non-motor phenotypes. Indeed, many non-motor signs in animals that may phenotypically resemble features in patients may be caused by different mechanisms or may not be consistent within the same or similar models. In this review, we survey the existing literature on the assessment of non-motor signs in parkinsonian rodents and non-human primates. We highlight the gaps in our understanding and suggest how researchers might improve experimental designs to produce more meaningful results with the hope of better understanding the disease and developing better therapies.

帕金森病是根据运动症状进行诊断的，但该疾病的非运动症状，如认知障碍、自主神经功能障碍、嗅觉减退、睡眠障碍和精神障碍等，会严重影响患者及其照护者的生活质量。要如实重现并量化这些非运动表型已被证明颇具挑战性。实际上，动物身上许多在表型上可能与患者特征相似的非运动体征，可能由不同机制引起，或者在相同或相似模型中可能并不一致。在这篇综述中，我们对现有关于帕金森病啮齿动物和非人灵长类动物非运动体征评估的文献进行了梳理。我们指出了目前认知上的空白，并就研究人员如何改进实验设计以获得更有意义的结果提出建议，以期更好地了解该疾病并开发出更有效的治疗方法。

REF: Wichmann T, Nelson A, Torres ERS, Svenningsson P, Marongiu R. Leveraging animal models to understand non-motor symptoms of Parkinson's disease. Neurobiol Dis. 2025;208:106848. doi:10.1016/j.nbd.2025.106848 PMID: 40023327

Vascular models of Alzheimer's disease: An overview of recent in vitro models of the blood-brain barrier

阿尔茨海默病的血管模型：血脑屏障近期体外模型概述

Alzheimer's disease (AD) remains an overwhelming epidemiologic and economic burden on our healthcare systems, affecting an estimate of 11 % of individuals aged 65 years and older. Increasing evidence of the role of the blood-brain barrier (BBB) in AD pathology lends support to the vascular hypothesis of AD, which posits that damage to cerebral vasculature and impairments to cerebral blood flow are major contributors to neurodegeneration in AD. While the question remains whether the dysfunction of the BBB is the cause or consequence of the disease, understanding of the relationship between vascular pathology and AD is growing increasingly complex, warranting the need for better tools to study vasculature in AD. This review provides an overview of AD models in the context of studying vascular impairments and their relevance in pathology. Specifically, we summarize opportunities in in vitro models, cell sources, and phenotypic observations in sporadic and familial forms of AD. Further, we describe recent advances in generating models which recapitulate in vivo characteristics of the BBB in AD through the use of microfluidics, induced pluripotent stem cells (iPSC), and organoid technologies. Finally, we provide a searchable database of reported cell-based models of pathogenic AD gene variants.

阿尔茨海默病（AD）仍然给我们的医疗系统带来了沉重的流行病学和经济负担，据估计，65岁及以上的人群中有11%受其影响。越来越多的证据表明血脑屏障（BBB）在AD病理机制中发挥作用，这为AD的血管假说提供了支持。该假说认为，脑血管损伤和脑血流障碍是AD神经退行性病变的主要原因。虽然血脑屏障功能障碍是该病的原因还是结果仍存在疑问，但对血管病变与AD之间关系的理解正变得日益复杂，因此迫切需要更好的工具来研究AD中的血管情况。本综述概述了在研究血管损伤背景下的AD模型及其在病理学中的相关性。具体而言，我们总结了体外模型、细胞来源以及散发性和家族性AD表型观察方面的研究机会。此外，我们介绍了通过微流控技术、诱导多能干细胞（iPSC）和类器官技术构建能够重现AD血脑屏障体内特征模型的最新进展。最后，我们提供了一个可检索的致病AD基因变异细胞模型数据库。

REF: Takeuchi LE, Kalia LV, Simmons CA. Vascular models of Alzheimer's disease: An overview of recent in vitro models of the blood-brain barrier. Neurobiol Dis. 2025;208:106864. doi:10.1016/j.nbd.2025.106864 PMID: 40089165

Vascular and glymphatic dysfunction as drivers of cognitive impairment in Alzheimer's disease: Insights from computational approaches

血管和类淋巴系统功能障碍作为阿尔茨海默病认知障碍的驱动因素：来自计算方法的见解

Alzheimer's disease (AD) is driven by complex interactions between vascular dysfunction, glymphatic system impairment, and neuroinflammation. Vascular aging, characterized by arterial stiffness and reduced cerebral blood flow (CBF), disrupts the pulsatile forces necessary for glymphatic clearance, exacerbating amyloid-beta (Aβ) accumulation and cognitive decline. This review synthesizes insights into the mechanistic crosstalk between these systems and explores their contributions to AD pathogenesis. Emerging machine learning (ML) tools, such as DeepLabCut and Motion sequencing (MoSeq), offer innovative solutions for analyzing multimodal data and enhancing diagnostic precision. Integrating ML with imaging and behavioral analyses bridges gaps in understanding vascular-glymphatic dysfunction. Future research must prioritize these interactions to develop early diagnostics and targeted interventions, advancing our understanding of neurovascular health in AD.

阿尔茨海默病（AD）是由血管功能障碍、类淋巴系统损伤和神经炎症之间的复杂相互作用所驱动的。以动脉僵硬度增加和脑血流量（CBF）减少为特征的血管老化，会破坏类淋巴清除所需的搏动性力量，加剧β-淀粉样蛋白（Aβ）的积累和认知衰退。本综述综合了对这些系统之间机制性串扰的见解，并探讨了它们对AD发病机制的影响。新兴的机器学习（ML）工具，如DeepLabCut和运动序列分析（MoSeq），为分析多模态数据和提高诊断精度提供了创新解决方案。将ML与影像学和行为分析相结合，有助于弥补对血管-类淋巴功能障碍理解上的差距。未来的研究必须优先关注这些相互作用，以开发早期诊断方法和有针对性的干预措施，增进我们对AD中神经血管健康的理解。

REF: Fatima G, Ashiquzzaman A, Kim SS, Kim YR, Kwon HS, Chung E. Vascular and glymphatic dysfunction as drivers of cognitive impairment in Alzheimer's disease: Insights from computational approaches. Neurobiol Dis. 2025;208:106877. doi:10.1016/j.nbd.2025.106877 PMID: 40107629

Joint analysis of single-cell RNA sequencing and bulk transcriptome reveals the heterogeneity of the urea cycle of astrocytes in glioblastoma

单细胞RNA测序与批量转录组联合分析揭示胶质母细胞瘤中星形胶质细胞尿素循环的异质性

Glioblastoma (GB) is incurable with a dismal prognosis. Single-cell RNA sequencing (scRNA-seq) is a pivotal tool for studying tumor heterogeneity. The dysregulation of the urea cycle (UC) frequently occurs in tumors, but its characteristics in GB have not been illuminated. This study integrated scRNA-seq UC scores and bulk RNA-seq data to build a GB prognostic model. We set up a novel prognostic model for predicting the survival of GB patients by integrating bulk RNA-seq and scRNA-seq data. The risk score was closely correlated with immune infiltration and drug sensitivity, pinpointing it as a promising independent prognostic factor.

胶质母细胞瘤（GB）无法治愈，预后不佳。单细胞RNA测序（scRNA-seq）是研究肿瘤异质性的关键工具。尿素循环（UC）失调在肿瘤中经常发生，但它在GB中的特征尚未明确。本研究整合了scRNA-seq的UC评分和批量RNA-seq数据，构建了GB预后模型。我们通过整合批量RNA-seq和scRNA-seq数据，建立了一种新的预测GB患者生存情况的预后模型。风险评分与免疫浸润和药物敏感性密切相关，表明它是一个有前景的独立预后因素。

REF: Tong M, Tu Q, Wang L, Chen H, Wan X, Xu Z. Joint analysis of single-cell RNA sequencing and bulk transcriptome reveals the heterogeneity of the urea cycle of astrocytes in glioblastoma. Neurobiol Dis. 2025;208:106835. doi:10.1016/j.nbd.2025.106835 PMID: 39938577

Potentiation of the M1 muscarinic acetylcholine receptor normalizes neuronal activation patterns and improves apnea severity in Mecp2+/− mice

增强M1毒蕈碱型乙酰胆碱受体可使Mecp2+/-小鼠的神经元激活模式恢复正常，并改善呼吸暂停严重程度

Rett syndrome (RTT) is a neurodevelopmental disorder that is caused by loss-of-function mutations in the methyl-CpG binding protein 2 (MeCP2) gene. RTT patients experience a myriad of debilitating symptoms, which include respiratory phenotypes that are often associated with lethality. Our previous work established that expression of the M1 muscarinic acetylcholine receptor (mAchR) is decreased in RTT autopsy samples, and that potentiation of the M1 receptor improves apneas in a mouse model of RTT; however, the population of neurons driving this rescue is unclear. Loss of Mecp2 correlates with excessive neuronal activity in cardiorespiratory nuclei. Since M1 is found on cholinergic interneurons, we hypothesized that M1-potentiating compounds decrease apnea frequency by tempering brainstem hyperactivity. To test this, Mecp2+/- and Mecp2+/+ mice were screened for apneas before and after administration of the M1 positive allosteric modulator (PAM) VU0453595 (VU595). Brains from the same mice were then imaged for c-Fos, ChAT, and Syto16 using whole-brain light-sheet microscopy to establish genotype and drug-dependent activation patterns that could be correlated with VU595's efficacy on apneas. The vehicle-treated Mecp2+/- brain exhibited broad hyperactivity when coupled with the phenotypic prescreen, which was significantly decreased by administration of VU595, particularly in regions known to modulate the activity of respiratory nuclei (i.e. hippocampus and striatum). Further, the extent of apnea rescue in each mouse showed a significant positive correlation with c-Fos expression in non-cholinergic neurons in the striatum, thalamus, dentate gyrus, and within the cholinergic neurons of the brainstem. These results indicate that Mecp2+/- mice are prone to hyperactivity in brain regions that regulate respiration, which can be normalized through M1 potentiation.

雷特综合征（RTT）是一种神经发育障碍性疾病，由甲基-CpG结合蛋白2（MeCP2）基因的功能丧失性突变引起。RTT患者会出现大量使人衰弱的症状，其中包括常与致死性相关的呼吸表型。我们之前的研究表明，RTT尸检样本中M1毒蕈碱型乙酰胆碱受体（mAchR）的表达降低，并且增强M1受体的功能可改善RTT小鼠模型的呼吸暂停；然而，介导这种改善作用的神经元群体尚不清楚。Mecp2的缺失与心肺呼吸核团中神经元活动过度有关。由于M1受体存在于胆碱能中间神经元上，我们推测M1增强型化合物通过抑制脑干过度活动来降低呼吸暂停频率。为了验证这一假设，我们在给予M1正变构调节剂（PAM）VU0453595（VU595）前后，对Mecp2+/-和Mecp2+/+小鼠的呼吸暂停情况进行了筛查。然后，使用全脑光片显微镜对同一批小鼠的大脑进行c-Fos、胆碱乙酰转移酶（ChAT）和Syto16成像，以确定与VU595改善呼吸暂停效果相关的基因型和药物依赖性激活模式。结合表型预筛查结果发现，接受溶媒处理的Mecp2+/-小鼠大脑呈现广泛的过度活动，而给予VU595后这种过度活动显著降低，尤其是在已知可调节呼吸核团活动的区域（即海马体和纹状体）。此外，每只小鼠呼吸暂停改善的程度与纹状体、丘脑、齿状回中的非胆碱能神经元以及脑干中的胆碱能神经元中c-Fos的表达呈显著正相关。这些结果表明，Mecp2+/-小鼠在调节呼吸的脑区易出现过度活动，而通过增强M1受体功能可使其恢复正常。

REF: Smith M, Dodis GE, Vanderplow AM, et al. Potentiation of the M1 muscarinic acetylcholine receptor normalizes neuronal activation patterns and improves apnea severity in Mecp2+/- mice. Neurobiol Dis. 2025;208:106859. doi:10.1016/j.nbd.2025.106859 PMID: 40021095

Impaired folate metabolism reshapes auditory response profiles and impairs loudness perception in MTHFR-deficient mice

叶酸代谢受损重塑亚甲基四氢叶酸还原酶（MTHFR）缺陷小鼠的听觉反应特征并损害响度感知

Folate metabolism, regulated by methylenetetrahydrofolate reductase (MTHFR), is crucial for proper neurodevelopment, and disruptions-whether due to genetic polymorphisms or maternal nutritional deficits-have been linked to cognitive and behavioral impairments. Notably, MTHFR-deficient mouse models display altered social interaction and auditory communication, hinting at disruptions in auditory-related circuits and prompting the question of whether impaired folate metabolism might also affect sound processing and perception. Here, using two-photon calcium imaging, we show that MTHFR deficiency increases both spontaneous and sound-evoked activity in the auditory cortex and significantly shifts neuronal response profiles, which in turn elevates perceived loudness while reducing sound-level discrimination. These findings underscore the potential role of compromised folate metabolism in driving the atypical auditory responses and may have broader relevance for understanding sensory dysfunction in various neurodevelopmental conditions.

由亚甲基四氢叶酸还原酶（MTHFR）调控的叶酸代谢对正常神经发育至关重要，而无论是由基因多态性还是母体营养缺乏导致的叶酸代谢紊乱，都与认知和行为障碍有关。值得注意的是，MTHFR缺陷的小鼠模型表现出社交互动和听觉交流的改变，这暗示了听觉相关回路存在紊乱，也引发了一个问题，即叶酸代谢受损是否也会影响声音处理和感知。在这里，我们通过双光子钙成像发现，MTHFR缺陷会增加听觉皮层的自发活动和声音诱发活动，并显著改变神经元反应特征，进而提高感知响度，同时降低声音强度辨别能力。这些发现强调了叶酸代谢受损在引发非典型听觉反应方面的潜在作用，并且对于理解各种神经发育疾病中的感觉功能障碍可能具有更广泛的意义。

REF: Sapir H, Bisharat G, Golan H, Resnik J. Impaired folate metabolism reshapes auditory response profiles and impairs loudness perception in MTHFR-deficient mice. Neurobiol Dis. 2025;208:106863. doi:10.1016/j.nbd.2025.106863 PMID: 40057124