Neurobiology of Disease最新文献_第8页

Astrocytic α7-nicotinic acetylcholine receptors mediate pain information processing and perception 星形胶质细胞α7-烟碱乙酰胆碱受体介导疼痛信息加工和感知。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-01 DOI: 10.1016/j.nbd.2025.107245

Teng Teng , Shaofan Yang , Jin Li , Haoyu Wang , Fengjuan Wu , Yong He , Jihua Fan , Hongwei Shi , Mingzhu Huang , Xiang Zhou , Ying Liu , Mingyue Gong , Chuanyan Yang , Huiquan Wang , Zhenlu Cai , Hongli Li , Kuan Zhang

The astrocyte–neuron network in the primary somatosensory cortex (S1) responds dynamically to pain stimuli and plays a pivotal role in pain processing. These stimuli activate astrocytic α7-nicotinic acetylcholine receptors (α7-nAChRs), yet their contribution to pain perception remains largely unclear. This study investigates the role of astrocytic α7-nAChRs in pain information processing and perception. Astrocytic α7-nAChRs were selectively deleted by injecting rAAV5-GfaABC₁D-NLS-Cre-P2A-mCherry into the S1 region of LoxP-Chrna7 transgenic mice or by tamoxifen administration in ALDH1-CreERT2:Chrna7^loxP/loxP mice. Immunohistochemistry was used to assess the expression of α7-nAChR and gliotransmitter d-serine. Astrocytic Ca²⁺ transients were monitored in vivo using two-photon Ca²⁺ imaging following AAV5-GfaABC₁D-cytoGCaMP6f-SV40 labeling. Neuronal Ca²⁺ transients in S1 evoked by plantar electric shock were recorded via fiber photometry in freely moving mice. Nociceptive and sensory behaviors were evaluated using hot plate and von Frey tests. Statistical analyses included Welch's t-tests for normally distributed data, Mann–Whitney U tests for non-normal data, and two-way ANOVA. Results showed that conditional deletion of α7-nAChRs in astrocytes markedly reduced d-serine levels within astrocytic territories. Two-photon Ca²⁺ imaging and fiber photometry revealed that α7-nAChR deletion attenuated both astrocytic Ca²⁺ transients and footshock-evoked neuronal Ca²⁺ activity in S1. Behaviorally, thermal pain responses were significantly impaired, whereas tactile thresholds and open-field behaviors were unaffected. These findings identify astrocytic α7-nAChRs in S1 facilitate d-serine levels and enhance astrocytic activity. Their physiological function is essential for pain-related information processing within astrocyte–neuron networks and plays a critical role in regulating pain perception.

初级体感觉皮层（S1）中的星形细胞-神经元网络对疼痛刺激作出动态反应，在疼痛加工中起关键作用。这些刺激激活星形细胞α7-烟碱乙酰胆碱受体（α7-nAChRs），但它们对疼痛感知的作用仍不清楚。本研究探讨星形细胞α7- nachr在疼痛信息加工和感知中的作用。通过在loxP - chrna7转基因小鼠S1区注射rAAV5-GfaABC1D-NLS-Cre-P2A-mCherry或在ALDH1-CreERT2:Chrna7loxP/loxP小鼠中给药他莫昔芬选择性地缺失星形胶质细胞α7-nAChRs。免疫组化法检测α7-nAChR和胶质递质d-丝氨酸的表达。在AAV5-GfaABC1D-cytoGCaMP6f-SV40标记后，使用双光子Ca2+成像在体内监测星形细胞Ca2+瞬态。用纤维光度法记录了自由运动小鼠足底电刺激引起的S1区神经元Ca2+瞬变。用热板测验和von Frey测验评估伤害和感觉行为。统计分析包括正态分布数据的Welch t检验，非正态数据的Mann-Whitney U检验和双向方差分析。结果表明，星形胶质细胞α7-nAChRs的条件缺失显著降低了星形胶质细胞区域内d-丝氨酸水平。双光子Ca2+成像和纤维光度法显示α7-nAChR缺失减弱了S1的星形细胞Ca2+瞬态和足震诱发的神经元Ca2+活性。行为学上，热痛反应明显受损，而触觉阈值和开放领域行为未受影响。这些发现表明S1中的α7-nAChRs促进d-丝氨酸水平并增强星形细胞活性。它们的生理功能在星形细胞-神经元网络中对疼痛相关信息的处理是必不可少的，在调节疼痛感知中起着关键作用。

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引用次数: 0

A novel conditional knock-in mouse model for APOE4-to-APOE3 switching 一种新的条件敲入小鼠apoe4 - apoe3转换模型。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-01 DOI: 10.1016/j.nbd.2025.107244

Ruoyi Ishikawa , Yu Yamazaki , Nayuta Nakazawa , Xin Li , Taku Tazuma , Yoshiko Takebayashi , Masahiro Nakamori , Yusuke Sotomaru , Hirofumi Maruyama

APOE polymorphisms are major genetic risk factors of Alzheimer's disease (AD). Compared with APOE3/E3, the APOE4/E4 genotype is associated with a > 14-fold increased risk. Therefore, we hypothesized that conversion of APOE4 to APOE3 would ameliorate AD-related pathologies. Accordingly, we generated a knock-in mouse model harboring an APOE4-FLEx (Flip-Excision) 4-to-3 construct enabling postnatal Cre-mediated APOE4-to-APOE3 switching. This construct comprised an APOE3 exon inserted in a reverse orientation downstream of the APOE4 exon, flanked by alternating loxP and mutant loxP sites, allowing Cre-mediated FLEx switching from APOE4-to-APOE3. For in vitro validation, HEK293T cells were transfected with APOE4-FLEx 4-to-3 plasmid, followed by AAV8-mediated iCre delivery. For in vivo studies, endogenous Apoe was replaced with the APOE4-FLEx 4-to-3 construct to generate APOE4-FLEx 4-to-3 knock-in mice, which were crossed with tamoxifen-inducible Rosa26-CreERT2 mice to yield Cre: APOE4-FLEx 4-to-3 double-knock-in mice. Tamoxifen was administered to induce APOE switching. Cre expression successfully induced APOE4-to-APOE3 switching in vitro. Tamoxifen administration in Cre: APOE4-FLEx 4-to-3 mice triggered APOE4-to-APOE3 switching in the liver, demonstrating the feasibility of postnatal isoform switching. However, brain APOE protein levels were below the detection limit. Investigation of the underlying cause involving transcript analysis revealed aberrant retention of intron 3 (APOE-I3). This abnormal splicing probably contributed to the decreased expression of fully spliced, translation-competent (mature) APOE mRNA, driving the subsequent protein reduction. Although APOE expression across organs in APOE4-FLEx 4-to-3 mice requires further optimization, our findings demonstrate that Cre-mediated FLEx switching can serve as a potential strategy to induce APOE genotype switching in vivo.

APOE多态性是阿尔茨海默病（AD）的主要遗传危险因素。与APOE3/E3相比，APOE4/E4基因型与 > 增加14倍的风险相关。因此，我们假设APOE4转化为APOE3可以改善ad相关病理。因此，我们建立了一个敲入小鼠模型，该模型具有APOE4-FLEx (Flip-Excision) 4-to-3结构，能够使出生后cre介导的APOE4-to-APOE3转换。该结构包括一个反向插入APOE4外显子下游的APOE3外显子，两侧是交替的loxP和突变的loxP位点，允许cre介导的从APOE4到APOE3的FLEx转换。为了进行体外验证，用APOE4-FLEx 4-to-3质粒转染HEK293T细胞，然后通过aav8介导的iCre传递。在体内研究中，将内源性Apoe替换为APOE4-FLEx 4-to-3构建体，生成APOE4-FLEx 4-to-3敲入小鼠，将其与他莫昔芬诱导的Rosa26-CreERT2小鼠杂交，产生Cre: APOE4-FLEx 4-to-3敲入小鼠。给药他莫昔芬诱导APOE转换。Cre表达成功诱导APOE4-to-APOE3在体外转换。Cre: APOE4-FLEx 4-to-3小鼠给予他莫昔芬可触发肝脏中APOE4-to-APOE3转换，证明了出生后亚型转换的可行性。然而，脑APOE蛋白水平低于检测限。对涉及转录分析的根本原因的调查揭示了内含子3 （APOE-I3）的异常保留。这种异常剪接可能导致完全剪接的翻译能力（成熟）APOE mRNA的表达减少，从而导致随后的蛋白质减少。虽然APOE在APOE4-FLEx 4-to-3小鼠的跨器官表达需要进一步优化，但我们的研究结果表明，cre介导的FLEx转换可以作为体内诱导APOE基因型转换的潜在策略。

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引用次数: 0

Glymphatic activity is linked to the synaptic vesicle cycle pathway in frontotemporal dementia: A metabolomics study 脑磷脂活性与额颞叶痴呆的突触囊泡循环通路有关：一项代谢组学研究。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-01 DOI: 10.1016/j.nbd.2025.107135

Min Chu, Ailing Yue, Haitian Nan, Hong Ye, Miao Qu, Liyong Wu

Background

Emerging evidence implicating glymphatic dysfunction contributes to the pathogenesis of frontotemporal dementia (FTD). However, the pathway correlated to glymphatic function in FTD remains poorly understood. We aimed to explore potential underlying metabolic pathways associated with glymphatic dysfunction in FTD.

Methods

We enrolled 37 behavior FTD (bvFTD) patients and 40 healthy controls. Glymphatic activity was assessed using diffusion tensor imaging data. Plasma metabolomic profiling was performed to identify glymphatic-associated metabolites, followed by pathway enrichment analysis. Additionally, the plasma biomarker was tested in a subset of 25 patients to validate the metabolite findings.

Results

Patients with bvFTD exhibited significantly altered metabolite profiles compared to controls. The glymphatic-associated metabolites were predominantly enriched in the synaptic vesicle cycle pathway (FDR p < 0.05). Furthermore, plasma neuropentraxin-2 (NPTX2) levels positively correlated with anterior glymphatic indices (r = 0.46, p = 0.027).

Conclusion

Our findings demonstrate the association between the glymphatic system and synaptic function in bvFTD.

背景：越来越多的证据表明，淋巴功能障碍与额颞叶痴呆（FTD）的发病有关。然而，FTD中与淋巴功能相关的途径仍然知之甚少。我们的目的是探索与FTD中淋巴功能障碍相关的潜在代谢途径。方法：选取37例行为性FTD （bvFTD）患者和40例健康对照。利用弥散张量成像数据评估淋巴活性。血浆代谢组学分析鉴定淋巴相关代谢物，随后进行途径富集分析。此外，在25名患者中测试了血浆生物标志物，以验证代谢物的发现。结果：与对照组相比，bvFTD患者表现出明显改变的代谢物谱。淋巴相关代谢物主要富集于突触囊泡循环通路（FDR p ）。结论：我们的研究结果表明，bvFTD中淋巴系统与突触功能之间存在关联。

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引用次数: 0

Protrudin acts at ER-endosome contacts to promote KIF5-mediated endosomal tubule fission 突起蛋白在内质网核内体接触处促进kif5介导的核内体小管裂变。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-01 DOI: 10.1016/j.nbd.2025.107231

Julia Kleniuk , Aishwarya G. Nadadhur , Catherine Rodger , Emily Wolfenden , Isabelle A. Hall , Samuel R. Cheers , Eliska Zlamalova , Evan Reid

Defective endosomal sorting and trafficking are increasingly recognised as key drivers of neurodegeneration, including hereditary spastic paraplegia (HSP) and other motor neuron disorders. Early endosomal tubule fission (ETF) is essential for sorting cargoes for recycling and retrograde transport, yet the mechanisms coordinating this process are incompletely defined. Here, we identify the endoplasmic reticulum (ER)–resident protein protrudin—previously shown to promote axonal regeneration after injury—as a key regulator of ETF. Using CRISPR interference in human cells, we show that loss of protrudin causes marked accumulation of elongated endosomal tubules, caused by defective fission. Protrudin-mediated ETF required its ability to interact with ER-localised VAP proteins, endosomal phosphoinositides, and the kinesin motor KIF5, indicating a function at ER–endosome contact sites. The endosomal tubulation phenotype depended on dynamic microtubules and dynein and was phenocopied by KIF5 depletion, suggesting that protrudin coordinates opposing microtubule motor forces to drive fission. Beyond this direct role, protrudin connects multiple ETF machineries implicated in lipid transfer, actin regulation, and ER shaping, positioning it as a central scaffold for ETF. Importantly, depletion of protrudin or the HSP-associated kinesin KIF5A produced similar endosomal tubulation defects in human cortical neurons, underscoring the neurophysiological and disease relevance of this pathway. These findings identify protrudin as a key molecular link between ER–endosome communication, neuronal membrane trafficking, and axonal maintenance—processes whose disruption underlies neurodegenerative disease.

有缺陷的内体分类和运输越来越被认为是神经变性的关键驱动因素，包括遗传性痉挛性截瘫（HSP）和其他运动神经元疾病。早期内体小管裂变（ETF）对于回收和逆行运输的货物分类至关重要，但协调这一过程的机制尚不完全明确。在这里，我们确定了内质网（ER）驻留蛋白突起-先前显示促进损伤后轴突再生-作为ETF的关键调节因子。在人类细胞中使用CRISPR干扰，我们发现突起蛋白的缺失导致由裂变缺陷引起的细长内体小管的显著积累。pronudin介导的ETF需要能够与内质网定位的VAP蛋白、内体磷酸肌苷和运动蛋白KIF5相互作用，表明其在内质网内体接触部位起作用。内体管化表型依赖于动态微管和动力蛋白，并通过KIF5耗竭得到表型，表明突起蛋白协调反对微管运动力来驱动裂变。除了这一直接作用外，突起蛋白还连接了涉及脂质转移、肌动蛋白调节和内质网形成的多个ETF机制，将其定位为ETF的中心支架。重要的是，在人类皮质神经元中，突起蛋白或热刺蛋白相关的激酶KIF5A的缺失产生了类似的内体管化缺陷，强调了该途径的神经生理学和疾病相关性。这些发现表明，突起蛋白是内质网内体通讯、神经元膜运输和轴突维持过程之间的关键分子链接，而轴突维持过程的破坏是神经退行性疾病的基础。

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引用次数: 0

Chemogenetic activation of oxytocinergic neurons rescues neural correlates of encephalopathy of prematurity in mice 催产素能神经元的化学发生激活可拯救小鼠早产儿脑病的神经相关细胞。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-01 DOI: 10.1016/j.nbd.2025.107250

Marit Knoop , Marie-Laure Possovre , Ece Trak , Jean-Luc Pitetti , Yohan van de Looij , Eduardo Sanches , Stergios Tsartsalis , Julien Pansiot , Gabriel Schirmbeck , Olivier Baud

Every year, 15 million babies are born preterm, putting them at increased risk of encephalopathy of prematurity (EoP). EoP is characterized by microglia-induced neuroinflammation, which can aggravate injury mechanisms leading to neuronal disorders, myelination delay, and subsequent functional consequences. While effective neuroprotective strategies in the preterm brain remain elusive, interventions such as skin-to-skin, developmental care, and music therapy have a positive impact on newborn brain development, potentially related to the oxytocinergic system. Endogenous oxytocin is recognized as a regulator of maternal-child social bonding, but its neuroprotective effect in the injured brain remains to be elucidated. Here, we investigated the effects of chemogenetic activation of oxytocinergic neurons on the neural correlates of EoP. Using a well-established mouse model of systemic interleukin-1β to induce EoP, we showed that neonatal chemogenetic activation of oxytocinergic neurons has anti-inflammatory effects in microglia, improving microstructural development of the corpus callosum and motor cortex, and rescuing typical social behavior. These neuroprotective effects were more pronounced in females, who showed a greater reduction in microgliosis and improved social behavior compared to males. This study provides a biological explanation for how developmental care and early interventions, linked to the oxytocinergic system, may induce neuroprotection in the developing brain.

每年有1500万婴儿早产，这增加了他们患早产脑病的风险。EoP以小胶质细胞诱导的神经炎症为特征，可加重损伤机制，导致神经元紊乱、髓鞘形成延迟和随后的功能后果。虽然有效的早产儿大脑神经保护策略仍然难以捉摸，但皮肤对皮肤、发育护理和音乐治疗等干预措施对新生儿大脑发育有积极影响，可能与催产素系统有关。内源性催产素被认为是母婴社会关系的调节因子，但其在损伤脑中的神经保护作用仍有待阐明。在这里，我们研究了催产素能神经元的化学激活对EoP神经相关细胞的影响。通过建立小鼠全身白介素-1β诱导EoP模型，我们发现新生儿化学发生激活催产素能神经元具有小胶质细胞的抗炎作用，促进胼胝体和运动皮层的微观结构发育，并挽救典型的社会行为。这些神经保护作用在女性身上更为明显，与男性相比，女性的小胶质瘤减少得更多，社交行为也有所改善。这项研究为与催产素系统相关的发育护理和早期干预如何在发育中的大脑中诱导神经保护提供了生物学解释。

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引用次数: 0

Retraction Notice to “Hypercholesterolemia-induced A accumulation in rabbit brain is associated with alteration in IGF-1 signaling” [Neurobiology of Disease 32 (2008) 426–432] 撤回“高胆固醇血症诱导的A在兔脑内的积累与IGF-1信号的改变有关”[神经生物学疾病32(2008)426-432]。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-01 DOI: 10.1016/j.nbd.2025.107204

Sunita Sharma, R.P. Jaya Prasanthi, Eric Schommer, Gwen Feist, Othman Ghribi

引用次数: 0

Chemogenetic control of GABAergic neurons within the interpeduncular nucleus reveals dissociable behavioral components of the nicotine withdrawal phenotype 脑梗间核gaba能神经元的化学发生控制揭示了尼古丁戒断表型的可解离行为成分。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-01 DOI: 10.1016/j.nbd.2025.107240

Anabel M.M. Miguelez Fernández, Shana Netherton, Seshadri B. Niladhuri, Alexander C. Brown, Patricia Rivera, Kuei Y. Tseng, Christian J. Peters

Chronic exposure to nicotine results in the development of a dependent state such that a withdrawal syndrome is elicited upon cessation of nicotine. The interpeduncular nucleus (IPN) contains a high concentration of nicotinic acetylcholine receptors (nAChRs) and has been identified as a key brain region involved in nicotine withdrawal. Here we investigated the contribution of two distinct subpopulations of IPN GABAergic neurons to nicotine withdrawal behaviors. Withdrawal was induced in mice by implantation of osmotic pumps containing nicotine, followed by precipitation by intraperitoneal injections of mecamylamine. Using a chemogenetic approach to specifically target Amigo1-expressing or Epyc-expressing neurons within the IPN, we found that activity of the Amigo1 subpopulation of GABAergic neurons is critical for anxiety-like behaviors both in naïve mice and in those undergoing nicotine withdrawal. Moreover, data revealed that stimulation of Amigo1 neurons in nicotine-naïve mice elicits opposite effects on affective and somatic behaviors. Taken together, these results suggest that somatic and affective behaviors constitute dissociable components of the nicotine withdrawal phenotype and are likely supported by distinct subpopulations of neurons within the IPN.

长期暴露于尼古丁导致依赖状态的发展，从而在停止尼古丁时引起戒断综合征。脑梗间核（IPN）含有高浓度的尼古丁乙酰胆碱受体（nachr），已被确定为参与尼古丁戒断的关键脑区。在这里，我们研究了两个不同的IPN gaba能神经元亚群对尼古丁戒断行为的贡献。通过植入含尼古丁的渗透泵诱导小鼠戒断，然后通过腹腔注射甲胺沉淀。利用化学遗传学方法特异性靶向IPN中表达Amigo1或表达epyc的神经元，我们发现gaba能神经元Amigo1亚群的活性对naïve小鼠和尼古丁戒断的小鼠的焦虑样行为至关重要。此外，数据显示nicotine-naïve小鼠Amigo1神经元的刺激对情感和躯体行为产生相反的影响。综上所述，这些结果表明，躯体和情感行为构成尼古丁戒断表型的可分离成分，并可能由IPN内不同的神经元亚群支持。

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引用次数: 0

Mitochondrial-associated endoplasmic reticulum membranes (MAMs) drive ferroptosis via redox signaling: A key potential mechanism in epilepsy 线粒体相关内质网膜（MAMs）通过氧化还原信号驱动铁吊：癫痫的一个关键潜在机制。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-01 DOI: 10.1016/j.nbd.2025.107248

Ruting Fu , Liya Fang , Jiahao Liu , Yuanyuan Liu , Yeyan Wang , Deming Kong , Jin Guo

Although targeting neuronal excitability remains the cornerstone of epilepsy treatment, the high prevalence of drug-resistant epilepsy compels a reexamination of its upstream mechanisms. Growing evidence identifies redox imbalance and specific cell death programs as key drivers of epileptogenesis. We propose a unified framework. Here, we position dysfunction of mitochondria-associated endoplasmic reticulum membranes (MAMs) linked to ferroptosis as a core pathogenic axis. Multiple epileptogenic triggers converge to pathologically remodel MAMs, transforming them into a catalytic platform that efficiently initiates ferroptosis. This is achieved through the nanoscale co-localization of calcium ions, reactive oxygen species, and unstable iron. We systematically dissect how MAMs integrate calcium signaling, lipid metabolism, and redox balance, and outline core ferroptosis pathways. Critically, MAMs remodeling subverts antioxidant defenses, reprograms lipid metabolism, and irreversibly drives ferroptosis. This MAMs-ferroptosis axis promotes epilepsy chronicity by mediating selective neuronal loss, amplifying neuroinflammation, and disrupting excitatory-inhibitory balance. Based on this mechanism, we propose a novel therapeutic paradigm: stabilizing MAMs upstream with Sigma-1 receptor ligands, combined with neutralizing lipid peroxides downstream using ferroptosis inhibitors. This multi-tiered strategy provides a foundation for developing disease-modifying, next-generation epilepsy therapies.

虽然靶向神经元兴奋性仍然是癫痫治疗的基石，但耐药癫痫的高患病率迫使人们重新审视其上游机制。越来越多的证据表明氧化还原失衡和特定的细胞死亡程序是癫痫发生的关键驱动因素。我们提出一个统一的框架。在这里，我们定位线粒体相关内质网膜（MAMs）功能障碍与铁死亡相关的核心致病轴。多种致痫触发汇聚到病理重塑mam，将它们转化为有效启动铁下垂的催化平台。这是通过钙离子、活性氧和不稳定铁的纳米级共定位实现的。我们系统地剖析了MAMs如何整合钙信号、脂质代谢和氧化还原平衡，并概述了核心的铁死亡途径。至关重要的是，MAMs重塑会破坏抗氧化防御，重编程脂质代谢，并不可逆转地驱动铁凋亡。mams -铁垂轴通过介导选择性神经元丢失、放大神经炎症和破坏兴奋-抑制平衡来促进癫痫的慢性性。基于这一机制，我们提出了一种新的治疗模式：用Sigma-1受体配体稳定上游的MAMs，结合使用铁下垂抑制剂中和下游的脂质过氧化物。这种多层策略为开发改善疾病的下一代癫痫疗法提供了基础。

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引用次数: 0

Tri-modal assessment reveals early visual pathway degeneration in patients with MSA-C 三模态评估显示MSA-C患者的早期视觉通路变性。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-01 DOI: 10.1016/j.nbd.2025.107243

Chunrong Wang , Feiyan Deng , Zhao Chen , Daji Chen , Linlin Wan , Zhe Long , Riwei Ouyang , Qi Wu , Qin Long , Jiawei He , Mengyuan Dong , Linliu Peng , Huirong Peng , Yuting Shi , Xuan Hou , Lang He , Rong Qiu , Beisha Tang , Hong Jiang

Background and objectives

Post-mortem evidence suggests neurodegeneration in the visual pathway in multiple system atrophy-cerebellar type (MSA-C), yet robust in vivo evidence remains scarce. This study aimed to characterize these visual pathway changes in MSA-C patients by integrating optical coherence tomography (OCT), visual evoked potential (VEP), and magnetic resonance imaging (MRI).

Methods

This cross-sectional study prospectively recruited 156 participants, including 53 healthy controls and 103 early-stage MSA-C patients (mean disease duration: approx. 2 years). All participants underwent retinal layer evaluation using OCT. A randomly selected subset of 34 MSA-C patients and 19 controls also received VEP and MRI to assess visual pathway structure and function comprehensively.

Results

OCT analysis revealed significant parafoveal thinning within the 3-mm inner ring in MSA-C patients, predominantly affecting the ganglion cell layer (GCL) (P < 0.001) and inner plexiform layer (IPL) (P < 0.001). VEP recordings demonstrated significantly prolonged P100 latency (P < 0.001). MRI confirmed reduced cerebellar volume (P < 0.001). DTI detected microstructural degeneration in the cerebellum and visual pathways, with increased mean and axial diffusivity in optic tracts and radiation. Notably, retinal thinning correlated significantly with longer P100 latency (GCL: r = 0.49, P = 0.003; IPL: r = 0.41, P = 0.015) and cerebellar atrophy (GCL: r = 0.53, P = 0.001; IPL: r = 0.49, P = 0.003), indicating integrated visual pathway degeneration.

Conclusions

This large-scale multimodal study provides robust in vivo evidence that MSA-C involves early retinal neurodegeneration, functional conduction delay, and central white matter degeneration. The convergence of OCT, VEP, and DTI parameters suggests bidirectional retinocortical degeneration. Our findings support the potential of these parameters for early detection and highlight the visual pathway as a promising potential biomarker in synucleinopathies.

背景和目的：死后证据提示多系统萎缩-小脑型（MSA-C）的视觉通路神经退行性变，但体内证据仍然缺乏。本研究旨在通过整合光学相干断层扫描（OCT）、视觉诱发电位（VEP）和磁共振成像（MRI）来表征MSA-C患者的这些视觉通路变化。方法：本横断面研究前瞻性地招募了156名参与者，包括53名健康对照者和103名早期MSA-C患者(平均病程：约。 2年)。随机选择34名MSA-C患者和19名对照者接受VEP和MRI，全面评估视觉通路结构和功能。结果：OCT分析显示MSA-C患者在3毫米内环内明显的中央窝旁变薄，主要影响神经节细胞层（GCL）（P ）。结论：这项大规模的多模式研究提供了强有力的体内证据，表明MSA-C涉及早期视网膜神经变性、功能性传导延迟和中枢白质变性。OCT、VEP、DTI参数趋同提示双向性视网膜皮质变性。我们的研究结果支持这些参数在早期检测中的潜力，并强调视觉通路作为突触核蛋白病的潜在生物标志物。

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引用次数: 0

Nerve injury promotes glial immune responses through a Draper/Ninjurin A pathway 神经损伤通过Draper/Ninjurin a通路促进神经胶质免疫反应。

IF 5.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2026-01-01 DOI: 10.1016/j.nbd.2025.107242

Cole R. Brashaw , Annie M. Griffin , Sean D. Speese , Mary A. Logan

Degenerating neurons elicit striking immune reactions from glial cells, including directed invasion of injury sites and engulfment of neuronal debris. While these conserved glial immune responses are neuroprotective, our mechanistic understanding of glial immunity in the damaged and diseased brain is still incomplete. Here, using an in vivo nerve injury assay in the adult Drosophila olfactory system, we characterize a novel role for the transmembrane adhesion molecule Ninjurin A (NijA). We show that NijA is transcriptionally upregulated in neuropil ensheathing glia, but not local astrocytes, within hours after olfactory nerve transection. In NijA mutants, glia fail to properly infiltrate areas that contain severed olfactory nerves, and degenerating axonal debris is not cleared from the CNS. One well-defined signaling cascade critical for ensheathing glial clearance of damaged olfactory axons is the conserved MEGF10/Draper pathway, which includes the engulfment receptor Draper, downstream transcriptional regulators Stat92E and AP-1, and their known gene target MMP-1. We show that injury-induced transcription of NijA in responding glia requires the Draper receptor, but not Stat92E, AP-1, or MMP-1, suggesting a parallel signaling cascade activated downstream of Draper. Our findings reveal an essential role for the glial adhesion factor NijA in morphological and phagocytic responses to CNS damage, highlighting this conserved molecule as a new potential glial therapeutic target for neurodegenerative conditions.

退化的神经元引起神经胶质细胞的强烈免疫反应，包括直接侵入损伤部位和吞噬神经元碎片。虽然这些保守的神经胶质免疫反应具有神经保护作用，但我们对受损和患病大脑中神经胶质免疫的机制理解仍然不完整。在此，通过对成年果蝇嗅觉系统的活体神经损伤实验，我们描述了跨膜粘附分子Ninjurin a （NijA）的新作用。我们发现，在嗅神经横断后数小时内，NijA在神经鞘胶质细胞中转录上调，而不是局部星形胶质细胞。在NijA突变体中，神经胶质细胞不能正常浸润含有切断嗅觉神经的区域，并且退化的轴突碎片不能从中枢神经系统中清除。保守的MEGF10/Draper通路是一个明确定义的信号级串，它包括吞噬受体Draper、下游转录调节因子Stat92E和AP-1，以及它们已知的基因靶点MMP-1。我们发现，神经胶质细胞中NijA的损伤诱导转录需要Draper受体，而不需要Stat92E、AP-1或MMP-1，这表明Draper下游有一个平行的信号级联被激活。我们的研究结果揭示了神经胶质粘附因子NijA在中枢神经系统损伤的形态学和吞噬反应中的重要作用，突出了这种保守分子作为神经退行性疾病的新的潜在神经胶质治疗靶点。

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