Experimental Neurology最新文献_第3页

Activation of oligodendrocyte precursor cells triggers cognitive dysfunction and synaptic defects in SAE 少突胶质前体细胞的激活引发SAE的认知功能障碍和突触缺陷

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-27 DOI: 10.1016/j.expneurol.2026.115670

You Wu , Zhengdong Yang , Huiqing Liu , Jin Li , Renhuai Liu , Yi Li , Yu Chen , Binxiao Su

Sepsis-associated encephalopathy (SAE) is defined as a diffuse neurological dysfunction that occurs secondary to sepsis, in the absence of direct central nervous system infection, and is associated with high rates of incidence, mortality, and disability. Despite its clinical significance, the neuropathological mechanisms underlying SAE are not yet fully understood, making its pathogenesis a focal point of ongoing research. Oligodendrocyte precursor cells (OPCs), which are the most proliferative cell type within the central nervous system, primarily contribute to the generation of mature oligodendrocytes and are integral to myelination and the maintenance of myelin. Nevertheless, the role and pathological changes of OPCs during the acute phase of SAE remain inadequately characterized. This study illustrates that OPCs in the hippocampal CA1 region may undergo immune activation under SAE conditions, characterized by significantly elevated inflammatory transcription and phagocytic capacity. Additionally, activated OPCs in SAE mice may contribute to the synaptic pruning of neurons. By generating PDGFRa-Cre/ERT transgenic mice and conducting stereotactic injections of pAAV-EGFP-flex-DTA virus into the hippocampal CA1 region to selectively ablate OPCs, we observed a significant enhancement in cognitive function in SAE mice. This improvement is likely due to the alleviation of synaptic structural and functional impairments in neurons. Our findings indicate that OPCs play a critical role in the pathogenesis of SAE, highlighting their potential as a novel therapeutic target for this condition.

脓毒症相关脑病（SAE）被定义为继发于脓毒症的弥漫性神经功能障碍，在没有直接中枢神经系统感染的情况下，与高发病率、死亡率和致残率相关。尽管具有临床意义，但SAE的神经病理机制尚未完全了解，因此其发病机制是正在进行的研究的焦点。少突胶质前体细胞（OPCs）是中枢神经系统中最具增殖能力的细胞类型，主要有助于成熟少突胶质细胞的产生，是髓鞘形成和髓磷脂维持的组成部分。然而，OPCs在SAE急性期的作用和病理变化仍然没有充分的描述。本研究表明，SAE条件下海马CA1区的OPCs可能发生免疫激活，其特征是炎症转录和吞噬能力显著升高。此外，SAE小鼠中活化的OPCs可能有助于神经元的突触修剪。通过生成pdgfr - cre /ERT转基因小鼠，并将pAAV-EGFP-flex-DTA病毒立体定向注射到海马CA1区，选择性地消融OPCs，我们观察到SAE小鼠的认知功能显著增强。这种改善可能是由于神经元突触结构和功能损伤的减轻。我们的研究结果表明，OPCs在SAE的发病机制中起着关键作用，突出了它们作为这种疾病的新治疗靶点的潜力。

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引用次数: 0

Integrated miRNA-proteomic profiling identifies chronic vesicle-trafficking and proteostasis disruptions after mild traumatic brain injury 综合mirna -蛋白质组学分析鉴定轻度创伤性脑损伤后的慢性囊泡运输和蛋白质平衡中断

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-26 DOI: 10.1016/j.expneurol.2026.115652

Hamad Yadikar , Mubeen A. Ansari

Background

Mild traumatic brain injury (mTBI) often produces persistent deficits, yet the molecular mechanisms driving chronic pathology remain undefined.

Objective

We aimed to identify mechanistic drivers of long-term dysfunction after mTBI by integrating proteomics, transcriptomics, and behavioral outcomes.

Methods

Adult rats were subjected to a modified Marmarou weight-drop mTBI model (diffuse closed-head injury) or a sham procedure. Cortical tissue was analyzed at 21 days post-injury (chronic phase) by quantitative proteomics and small RNA sequencing, while neurological and motor functions were tracked longitudinally (subacute to chronic phases). Key molecular changes were validated via Western blotting and RT-qPCR.

Results

mTBI induced widespread and persistent alterations in cortical protein expression, particularly affecting vesicle-trafficking and proteostasis-related pathways. Several proteins—including Rab11b, Dnm2, TIA1, Snx30, Sbf1, and Vma21—exhibited robust decreases across both proteomic and immunoblot analyses, indicating reproducible impairment of endosomal recycling and stress-response mechanisms. Cavin-2 and COMMD2 showed significant fold changes at the proteomic level but were not entirely validated and therefore remain preliminary observations. Differentially expressed miRNAs exhibited coordinated regulatory patterns, and integrated miRNA–protein signatures achieved high discriminatory performance (AUC > 0.95) in separating injured from control animals.

Conclusions

These findings demonstrate that even an mTBI causes enduring disruptions in protein homeostasis, vesicle trafficking, and post-transcriptional regulation, which correlate with chronic behavioral deficits. The injury-responsive networks identified provide a systems-level foundation for future mechanistic studies and highlight promising candidate biomarkers to improve mTBI diagnosis and monitoring.

背景：轻度创伤性脑损伤（mTBI）经常产生持续的缺陷，但驱动慢性病理的分子机制尚不清楚。目的：我们旨在通过整合蛋白质组学、转录组学和行为结果来确定mTBI后长期功能障碍的机制驱动因素。方法采用改良Marmarou减重mTBI模型（弥漫性闭合性头部损伤）或假手术治疗成年大鼠。通过定量蛋白质组学和小RNA测序分析损伤后21天（慢性期）的皮质组织，同时纵向追踪神经和运动功能（亚急性期至慢性期）。通过Western blotting和RT-qPCR验证关键分子变化。结果脑外伤引起皮质蛋白表达的广泛和持续改变，特别是影响囊泡运输和蛋白固定相关途径。包括Rab11b、Dnm2、TIA1、Snx30、Sbf1和vma21在内的几种蛋白质在蛋白质组学和免疫印迹分析中均表现出明显的减少，表明内体循环和应激反应机制的可重复性损伤。Cavin-2和COMMD2在蛋白质组学水平上显示出显著的折叠变化，但尚未完全验证，因此仍然是初步观察结果。差异表达的mirna表现出协调的调控模式，整合的mirna -蛋白特征在区分受伤动物和对照动物方面具有很高的歧视性（AUC > 0.95）。这些发现表明，即使是mTBI也会导致蛋白质稳态、囊泡运输和转录后调控的持续中断，这些都与慢性行为缺陷有关。确定的损伤反应网络为未来的机制研究提供了系统级基础，并突出了有希望的候选生物标志物，以改善mTBI的诊断和监测。

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引用次数: 0

Low-frequency TMS ameliorates neonatal hypoxia-ischemia injury by normalizing glutamatergic transmission in penumbra 低频经颅磁刺激通过调节半暗区谷氨酸能传递改善新生儿缺氧缺血损伤。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-25 DOI: 10.1016/j.expneurol.2026.115669

Ivan Goussakov, Sylvia Synowiec, Alexander Drobyshevsky

Perinatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of morbidity and mortality in term neonates. The current standard of care, therapeutic hypothermia, provides only partial neuroprotection. This study investigates the potential of low-frequency transcranial magnetic stimulation (LF-TMS) as a novel non-pharmacological adjunct therapy by targeting a key pathological mechanism of HIE: a persistent, pathological increase in glutamatergic synaptic transmission, or hypoxic long-term potentiation.

Using a neonatal mouse model of hypoxia-ischemia, we administered a single session of LF-TMS 30 min after the hypoxic event. We then evaluated its effects on synaptic function via slice electrophysiology and on brain injury volume using serial MRI. Our results show that hypoxia-ischemia induced significant and lasting synaptic potentiation in the perilesional region of the somatosensory cortex. LF-TMS treatment successfully reduced this elevated glutamatergic response to control levels, suggesting a therapeutic mechanism similar to long-term depression and/or depotentiation by downregulating AMPA receptors.

LF-TMS provided significant neuroprotection, as demonstrated by reductions in volumes of the ischemic core and penumbra 48 h after the injury. LF-TMS did not alter excitability in sham-treated mice, confirming its safety as a targeted intervention for pathological conditions without affecting normal brain function. This study supports that LF-TMS is a promising neuroprotective strategy that mitigates brain injury in a neonatal hypoxia-ischemia model.

围产期缺氧缺血性脑病（HIE）是足月新生儿发病和死亡的主要原因。目前的护理标准，治疗性低温，只能提供部分神经保护。本研究探讨了低频经颅磁刺激（LF-TMS）作为一种新的非药物辅助治疗的潜力，通过针对HIE的一个关键病理机制：持续的、病理性的谷氨酸突触传递增加，或缺氧长期增强。使用新生小鼠缺氧缺血模型，我们在缺氧事件后30 min给予单次LF-TMS。然后，我们通过切片电生理评估其对突触功能的影响，并通过序列MRI评估其对脑损伤体积的影响。我们的研究结果表明，缺氧缺血在体感觉皮层的病灶周围区域诱导了显著和持久的突触增强。LF-TMS治疗成功地将这种升高的谷氨酸反应降低到控制水平，表明其治疗机制类似于通过下调AMPA受体的长期抑郁和/或去强化。LF-TMS提供了显著的神经保护作用，损伤后48 h缺血核心和半暗带的体积减少。LF-TMS没有改变假药治疗小鼠的兴奋性，证实了其作为病理条件的靶向干预的安全性，而不影响正常的脑功能。本研究支持LF-TMS是一种很有前途的神经保护策略，可以减轻新生儿缺氧缺血模型的脑损伤。

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引用次数: 0

Ectopically overexpressed glycine transporter 2 contributes to epileptogenesis in DEPDC5-related epilepsy 异位过表达的甘氨酸转运蛋白2参与depdc5相关癫痫的发生。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-24 DOI: 10.1016/j.expneurol.2026.115668

Tao Yang , Rajat Banerjee , Mirte Scheper , Mi Jiang , Steven Dai , Eleonora Aronica , Yu Wang

Loss-of-function mutations in DEPDC5 (DEP domain-containing protein 5), a critical negative regulator of mTORC1 (mechanistic Target of Rapamycin Complex 1), are often identified in patients with refractory epilepsy. To understand its underlying pathogenesis and develop novel therapeutics, we used a highly clinically relevant rat model of DEPDC5-related epilepsy and resected human patient tissues to profile the molecular architecture in the dysplastic cortex. We report here that Slc6a5 (solute carrier family 6 member 5 gene), a marker gene for glycinergic inhibitory neurons, is ectopically overexpressed in mutant excitatory neurons in both experimental animal and human tissues. Using CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) in utero electroporation (IUE) to simultaneously knock out Depdc5 and Slc6a5 in forebrain excitatory neurons reduces seizure frequency and duration. These data suggest that SLC6A5 plays an important role in the epileptogenesis of DEPDC5-related epilepsy, although the underlying mechanisms remain unclear.

DEPDC5 （DEP结构域蛋白5）是mTORC1（雷帕霉素复合体1的机制靶点）的关键负调节因子，其功能缺失突变常在难固性癫痫患者中发现。为了了解其潜在的发病机制并开发新的治疗方法，我们使用了一个具有高度临床相关性的大鼠depdc5相关癫痫模型，并切除了人类患者组织来分析发育不良皮层的分子结构。我们在这里报道Slc6a5（溶质载体家族6成员5基因）是甘氨酸能抑制性神经元的标记基因，在实验动物和人类组织中突变的兴奋性神经元中异位过表达。在子宫电穿孔（IUE）中使用CRISPR （Clustered Regularly Interspaced Short Palindromic Repeats）同时敲除前脑兴奋性神经元中的Depdc5和Slc6a5，可减少癫痫发作的频率和持续时间。这些数据表明，SLC6A5在depdc5相关癫痫的癫痫发生中起重要作用，尽管其潜在机制尚不清楚。

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引用次数: 0

Mismatch between oxygen delivery and consumption in the cerebral watershed during subacute global hypoperfusion 亚急性全脑灌注不足时脑分水岭氧输送和耗氧量的不匹配。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-23 DOI: 10.1016/j.expneurol.2026.115666

Baoqiang Li , Hewei Cao , Hajime Takase , Srinivasa Rao Allu , Yimeng Wu , Buyin Fu , Sergei A. Vinogradov , Eng H. Lo , Ken Arai , Cenk Ayata , Sava Sakadžić

Hemodynamically significant carotid artery stenosis is a common clinical condition that can lead to chronic cerebral hypoperfusion. Despite the well-recognized pivotal role of pial collaterals in maintaining cerebral perfusion during focal arterial occlusions, regulation of microvascular blood flow and oxygenation in the cerebral watershed “pial-collateral territory” during chronic hypoperfusion remains unexplored. To answer this question, we applied 2-photon microscopy and Doppler optical coherence tomography to assess the changes in cerebral blood flow, capillary red-blood-cell (RBC) flux, and intravascular oxygen partial pressure (PO₂), seven days after bilateral common-carotid artery stenosis (BCAS). The measurements were performed in the middle-cerebral-artery (MCA) territory and the watershed between the MCA and anterior-cerebral-artery territories in the awake, head-restrained C57BL/6 mice, through a glass-sealed cranial window. The results showed that BCAS induced a significant decrease in microvascular perfusion in the watershed area compared to the MCA territory, with the largest RBC flux reduction observed in the subcortical white matter. The watershed area exhibited a larger drop between arterial and venous PO₂ and the calculated oxygen saturation, indicating a significant increase in oxygen extraction fraction following BCAS. Structural analysis of the microvasculature showed significant BCAS-induced dilation of pial collaterals, suggesting a potential compensatory mechanism to improve blood flow in the hypoperfused watershed. However, microvascular morphology did not change in either region, implying an absence of structural remodeling at this early stage. Collectively, these findings point to an oxygen supply-consumption mismatch and heightened vulnerability in the watershed areas, particularly affecting the subcortical white matter, during flow-limiting cervical artery stenosis.

血流动力学上显著的颈动脉狭窄是一种常见的临床状况，可导致慢性脑灌注不足。尽管公认脑侧支在局灶性动脉闭塞时维持脑灌注中的关键作用，但慢性脑灌注不足时脑分水岭“脑侧支区域”的微血管血流和氧合调节仍未被探索。为了回答这个问题，我们应用双光子显微镜和多普勒光学相干断层扫描来评估双侧颈总动脉狭窄（BCAS）后7天脑血流、毛细血管红细胞（RBC）通量和血管内氧分压（PO2）的变化。测量是在清醒、头部受限的C57BL/6小鼠的大脑中动脉（MCA）区域以及MCA和大脑前动脉区域之间的分水岭，通过玻璃密封的颅窗进行的。结果显示，与MCA区域相比，BCAS诱导分水岭区域微血管灌注显著减少，其中皮层下白质的红细胞通量减少最大。流域动脉和静脉PO2与计算的氧饱和度之间的下降幅度较大，表明BCAS后氧提取分数显著增加。微血管的结构分析显示，bcas显著诱导了头侧络的扩张，这表明一种潜在的代偿机制可以改善低灌注分水岭的血流。然而，这两个区域的微血管形态都没有改变，这意味着在早期阶段没有结构重塑。总的来说，这些发现表明，在限流颈动脉狭窄期间，分水岭区域的氧气供应-消耗不匹配和脆弱性增加，特别是对皮质下白质的影响。

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引用次数: 0

Exosomes-mediated delivery of miR-27a-3p antagomir alleviates white matter injury by regulating PPARγ/PRDX1/JNK pathway after subarachnoid hemorrhage in rats 外泌体介导的miR-27a-3p antagomir通过调节大鼠蛛网膜下腔出血后的PPARγ/PRDX1/JNK通路减轻白质损伤。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-23 DOI: 10.1016/j.expneurol.2026.115667

Zhaosi Zhang , Fuming Liang , Daochen Wen , Hong Chen , Nina Gu , Zhao Li , Lin Wang , Yingwen Wang , Qiuling Pan , Yajun Zhu , Dan Xu , Xiaochuan Sun , Chongjie Cheng , Jin Yan

White matter injury (WMI) is a critical factor contributing to poor neurological outcomes following subarachnoid hemorrhage (SAH). MicroRNAs (miRNAs) are key regulators of WMI-related pathology and can be delivered via exosomes, yet their mechanisms and therapeutic potential remain largely unexplored. In this study, miRNA sequencing revealed a significant upregulation of miR-27a-3p in peripheral blood exosomes after SAH, which was further confirmed in white matter tissue. BV2 cell–derived exosomes loaded with miR-27a-3p antagomir were administered intranasally and effectively targeted oligodendrocytes. Treatment with these exosomes alleviated WMI by reducing oligodendrocyte apoptosis and promoting the proliferation and differentiation of oligodendrocyte precursor cells, leading to improved neurological and electrophysiological recovery. Mechanistically, miR-27a-3p inhibited PPARγ, resulting in downregulation of PRDX1 and activation of the JNK pathway, which triggered oligodendrocyte apoptosis. These findings demonstrate that exosome-mediated delivery of miR-27a-3p antagomir mitigates SAH-induced WMI through modulation of the PPARγ/PRDX1/JNK axis, providing a promising noninvasive therapeutic approach for enhancing white matter repair and functional recovery after SAH.

脑白质损伤（WMI）是导致蛛网膜下腔出血（SAH）后神经预后不良的关键因素。microrna （mirna）是wmi相关病理的关键调节因子，可通过外泌体传递，但其机制和治疗潜力在很大程度上仍未被探索。在本研究中，miRNA测序显示SAH后外周血外泌体中miR-27a-3p显著上调，这在白质组织中得到进一步证实。携带miR-27a-3p antagomir的BV2细胞衍生外泌体经鼻给药并有效靶向少突胶质细胞。这些外泌体通过减少少突胶质细胞凋亡和促进少突胶质前体细胞的增殖和分化来减轻WMI，从而改善神经和电生理恢复。在机制上，miR-27a-3p抑制PPARγ，导致PRDX1下调和JNK通路激活，从而引发少突胶质细胞凋亡。这些发现表明，外泌体介导的miR-27a-3p antagomir通过调节PPARγ/PRDX1/JNK轴减轻了SAH诱导的WMI，为增强SAH后白质修复和功能恢复提供了一种有希望的非侵入性治疗方法。

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引用次数: 0

Molecular and biochemical insights into dysregulation of glycosphingolipid metabolism in a mouse model of lysosomal free sialic acid storage disorder 溶酶体游离唾液酸储存障碍小鼠模型中糖鞘脂代谢失调的分子和生化见解。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-22 DOI: 10.1016/j.expneurol.2026.115665

Marya S. Sabir , Mahin S. Hossain , Laura Pollard , Petcharat Leoyklang , Marjan Huizing , William A. Gahl , Frances M. Platt , May Christine V. Malicdan

Free sialic acid storage disorder (FSASD) is caused by pathogenic biallelic variants in SLC17A5, which encodes the lysosomal sialic acid exporter, sialin. FSASD is characterized by the accumulation of lysosomal free sialic acid, leading to either a severe, childhood-lethal form or a more slowly progressive neurodegenerative disorder associated with the p.Arg39Cys (p.R39C) variant, i.e., Salla disease. While dysregulated glycosphingolipid (GSL) metabolism has been observed in cellular models of FSASD, this study provides the first in vivo biochemical dissection of GSL metabolism in a knock-in mouse model harboring the Slc17a5 p.R39C variant. We employed an integrated multi-modal approach, including sialic acid quantification, exploratory untargeted lipidomics, HPLC-based GSL profiling, bulk transcriptomics, and 4-MU-based lysosomal enzyme activity assays in brain and peripheral tissues (liver and kidney). Exploratory untargeted lipidomic screening revealed region-dependent lipid alterations, with more pronounced changes in the cerebellum than in the forebrain. Pathway-level analyses indicated enrichment of lipid classes related to sphingolipid and GSL metabolism. Targeted biochemical analyses demonstrated that several GSL species accumulate predominantly in the brain, with minimal changes in peripheral tissues, whereas glucosylceramide levels were significantly reduced in all brain regions analyzed. Transcriptomic profiling identified dysregulation of several genes involved in GSL and sialic acid metabolism. Enzyme activity assays corroborated the transcriptomic findings, demonstrating increased activity of several lysosomal glycohydrolases, including neuraminidase 1/3/4 and β-hexosaminidase. Collectively, these findings highlight dysregulated GSL metabolism as a prominent biochemical consequence of sialin deficiency in vivo and highlight its putative role in FSASD neuropathology.

游离唾液酸储存障碍（fssd）是由SLC17A5的致病变异引起的，SLC17A5编码溶酶体唾液酸输出蛋白sialin。fssd的特点是溶酶体游离唾液酸的积累，导致严重的儿童致死形式或与p.a arg39cys （p.R39C）变异相关的进展较慢的神经退行性疾病，即Salla病。虽然在fssd的细胞模型中已经观察到糖鞘脂（GSL）代谢失调，但本研究首次在含有Slc17a5 p.R39C变体的敲入小鼠模型中对GSL代谢进行了体内生化解剖。我们采用了综合的多模式方法，包括唾液酸定量、探索性非靶向脂质组学、基于高效液相色谱的GSL分析、大量转录组学和基于4- mu的脑和外周组织（肝脏和肾脏）溶酶体酶活性测定。探索性非靶向脂质组学筛查显示区域依赖性脂质改变，小脑的变化比前脑的变化更明显。途径水平分析表明，与鞘脂和GSL代谢相关的脂类富集。有针对性的生化分析表明，几种GSL主要在大脑中积累，外周组织的变化很小，而葡萄糖神经酰胺水平在所有分析的大脑区域都显着降低。转录组学分析鉴定了参与GSL和唾液酸代谢的几个基因的失调。酶活性分析证实了转录组学的发现，表明几种溶酶体糖水解酶的活性增加，包括神经氨酸酶1/3/4和β-己糖氨酸酶。总的来说，这些发现强调了GSL代谢失调是体内唾液素缺乏的一个突出的生化后果，并强调了它在fssd神经病理学中的推测作用。

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引用次数: 0

Microglial P2RY12 mediates migration to and protection of cerebral microvasculature after ischemia–reperfusion via Caveolin-1 小胶质细胞P2RY12通过Caveolin-1介导缺血再灌注后脑微血管的迁移和保护

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-21 DOI: 10.1016/j.expneurol.2026.115662

Yuan Wang , Xiaoyan Li , Weijie Li , Chenglong Wang , Ge Xu , Shanshan Yu

Disruption of blood-brain barrier (BBB) integrity after cerebral ischemia-reperfusion (I/R) injury contributes to neuroinflammation and neuronal damage. Microglia plays a significant role in the repair processes of the BBB, and the G protein-coupled receptor P2RY12 is involved in microglial chemotactic migration. However, its precise function and associated downstream mechanisms are unclear. Caveolin-1 (Cav-1), a membrane scaffold protein, plays a key role in signal transduction and cellular motility. This study employed in vivo and in vitro experimental models to explore the functional role of the P2RY12-Cav-1 interaction after ischemic stroke. Blocking P2RY12 with PSB0739 worsened neurological deficits and BBB disruption. In contrast, the P2RY12 agonist 2MeSADP attenuated I/R injury, promoted Bv2 cell migration. Disrupting lipid rafts with methyl-β-cyclodextrin (MβCD) abolished these benefits. Co-immunoprecipitation verified P2RY12 interacts with the scaffolding domain of Cav-1. These findings reveal a possible mechanism by which the P2RY12-Cav-1 signaling axis regulates microglial chemotaxis for microvascular protection, offering a potential therapeutic target for the treatment of ischemic stroke.

脑缺血再灌注（I/R）损伤后血脑屏障（BBB）完整性的破坏有助于神经炎症和神经元损伤。小胶质细胞在血脑屏障的修复过程中发挥重要作用，G蛋白偶联受体P2RY12参与小胶质细胞趋化迁移。然而，其确切的功能和相关的下游机制尚不清楚。Caveolin-1 （Cav-1）是一种膜支架蛋白，在信号转导和细胞运动中起关键作用。本研究通过体内和体外实验模型探讨P2RY12-Cav-1相互作用在缺血性脑卒中后的功能作用。用PSB0739阻断P2RY12会加重神经功能缺损和血脑屏障破坏。相比之下，P2RY12激动剂2MeSADP减轻I/R损伤，促进Bv2细胞迁移。用甲基-β-环糊精（m -β cd）破坏脂筏可以消除这些益处。共免疫沉淀证实P2RY12与Cav-1的支架结构域相互作用。这些发现揭示了P2RY12-Cav-1信号轴调控小胶质细胞趋化以保护微血管的可能机制，为缺血性卒中的治疗提供了潜在的治疗靶点。

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引用次数: 0

Palmitoylethanolamide ameliorates postoperative cognitive dysfunction via microglial PPARα-mediated anti-inflammatory and neuroprotective mechanisms 棕榈酰乙醇酰胺通过小胶质细胞ppar α介导的抗炎和神经保护机制改善术后认知功能障碍。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-21 DOI: 10.1016/j.expneurol.2026.115664

Xiaojun Zhang , Wensi Wu , Zhenzhen Zheng , Guijie Liu , Dongliang Li , Liang Li

Background

Postoperative cognitive dysfunction (POCD) is a frequent neurological complication characterized by memory and learning impairments in the elderly, while effective pharmacological interventions remain limited. Palmitoylethanolamide (PEA), an endogenous lipid mediator with anti-inflammatory and neuroprotective properties, has emerged as a potential therapeutic candidate.

Methods

An aged mouse model of POCD was used to evaluate the effects of PEA. Cognitive performance was assessed by the open field test, novel object recognition, and Barnes maze. Neuroinflammation, microglial activation, neuronal integrity, and synaptic plasticity–related proteins were assessed using immunostaining and molecular analyses both in vivo and in vitro. To determine the role of peroxisome proliferator-activated receptor-α (PPARα), stereotaxic delivery of shPPARα virus to prefrontal cortex (PFC) microglia was performed.

Results

PEA treatment significantly improved both short- and long-term memory in aged POCD mice. Mechanistically, PEA attenuated microglial activation, shifted microglial activation toward the anti-inflammatory phenotype, preserved neuronal survival, and upregulated synaptic plasticity-associated proteins. Importantly, PEA restored PPARα activity, and knockdown of PPARα abolished these protective effects both in vivo and in vitro, confirming its essential role.

Conclusions

PEA alleviates cognitive deficits in aged POCD mice by enhancing PPARα signaling, reducing neuroinflammation, and promoting neuronal protection. These findings support PEA as a promising therapeutic strategy for the treatment of aged POCD.

背景：术后认知功能障碍（POCD）是老年人常见的以记忆和学习障碍为特征的神经系统并发症，而有效的药物干预仍然有限。棕榈酰乙醇酰胺（PEA）是一种内源性脂质介质，具有抗炎和神经保护作用，已成为潜在的治疗候选药物。方法：采用老年小鼠POCD模型评价PEA的作用。认知表现通过开放场测试、新物体识别和巴恩斯迷宫进行评估。利用免疫染色和分子分析在体内和体外评估神经炎症、小胶质细胞激活、神经元完整性和突触可塑性相关蛋白。为了确定过氧化物酶体增殖物激活受体-α (PPARα)的作用，将shPPARα病毒立体定向递送至前额皮质（PFC）小胶质细胞。结果：PEA治疗可显著改善老年POCD小鼠的短期和长期记忆。从机制上讲，PEA减弱了小胶质细胞的激活，将小胶质细胞的激活转向抗炎表型，保持了神经元的存活，并上调了突触可塑性相关蛋白。重要的是，PEA恢复了PPARα的活性，而敲低PPARα在体内和体外都消除了这些保护作用，证实了PEA的重要作用。结论：PEA通过增强PPARα信号，减少神经炎症，促进神经元保护，减轻老年POCD小鼠的认知缺陷。这些发现支持PEA作为治疗老年POCD的有希望的治疗策略。

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引用次数: 0

Role of glycolysis-mediated histone lactylation in microglial activation and progression of neurodegenerative diseases 糖酵解介导的组蛋白乳酸化在神经退行性疾病的小胶质细胞激活和进展中的作用。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-01-21 DOI: 10.1016/j.expneurol.2026.115663

Shuaikang Wang , Jingjing Wang , Zhiying Hu , Li Wu , Liping Huang

Microglia-mediated neuroinflammation is a key driver of neurodegenerative disease progression, yet the metabolic mechanisms underlying microglial dysfunction remain poorly understood. Recent studies highlight glycolytic reprogramming in activated microglia, which generates lactate that, in turn, promotes histone lactylation, an epigenetic modification that significantly alters gene expression. This glycolysis-histone lactylation axis has been implicated in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders, where its dysregulation exacerbates chronic neuroinflammation and neuronal damage. Despite this, the precise molecular mechanisms linking microglial metabolic shifts to epigenetic remodeling and disease pathogenesis are not fully defined. This review consolidates current knowledge on how the glycolysis-histone lactylation pathway influences microglial phenotypes and function in neurodegenerative contexts. We explore the molecular machinery driving lactate-mediated histone modifications, their transcriptional consequences, and their pathological impact on disease progression. Importantly, we discuss emerging therapeutic strategies targeting this metabolic-epigenetic axis, including glycolysis inhibitors and lactylation modulators, as promising precision medicine approaches for neurodegenerative diseases. By elucidating these mechanisms, this review provides a framework for developing metabolism-based interventions aimed at restoring microglial homeostasis and slowing neurodegeneration.

小胶质细胞介导的神经炎症是神经退行性疾病进展的关键驱动因素，然而小胶质细胞功能障碍背后的代谢机制仍然知之甚少。最近的研究强调了激活的小胶质细胞中的糖酵解重编程，它产生乳酸，进而促进组蛋白乳酸化，这是一种显着改变基因表达的表观遗传修饰。这种糖酵解-组蛋白乳酸化轴与阿尔茨海默病、帕金森病和其他神经退行性疾病有关，其失调加剧了慢性神经炎症和神经元损伤。尽管如此，将小胶质细胞代谢转变与表观遗传重塑和疾病发病机制联系起来的精确分子机制尚未完全确定。这篇综述巩固了目前关于糖酵解-组蛋白乳酸化途径如何影响神经退行性背景下的小胶质细胞表型和功能的知识。我们探索驱动乳酸介导的组蛋白修饰的分子机制，它们的转录后果，以及它们对疾病进展的病理影响。重要的是，我们讨论了针对这一代谢-表观遗传轴的新兴治疗策略，包括糖酵解抑制剂和乳酸化调节剂，作为神经退行性疾病的有前途的精准医学方法。通过阐明这些机制，本综述为开发以代谢为基础的干预措施提供了一个框架，旨在恢复小胶质细胞稳态和减缓神经变性。

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引用次数: 0