Experimental Neurology最新文献_第10页

Azeliragon attenuates cerebral infarction aggravation in diabetic rats: Receptor for advanced glycation end-product as a novel therapeutic target azelagon减轻糖尿病大鼠脑梗死加重：晚期糖基化终产物受体作为一种新的治疗靶点。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-03-01 Epub Date: 2025-12-09 DOI: 10.1016/j.expneurol.2025.115588

Jin Soo Lee , Bok Seon Yoon , Seong-Joon Lee , So Young Park , Eun Hye Joe , Young J. Oh , Eui-Ju Choi

Diabetes mellitus contributes to neurological deterioration in acute ischemic stroke; nonetheless, rapid glucose control strategies have proven ineffective in clinical trials. We investigated whether targeting the receptor for advanced glycation end products (RAGE) could prevent infarction worsening in diabetic cerebral ischemia. To generate a diabetic model, streptozotocin (50 mg/kg) was intraperitoneally injected into male Sprague–Dawley rats (7–8 weeks old). A transient 30-min middle cerebral artery occlusion was performed at 34 days after diabetes induction. Azeliragon (10 mg/kg), a RAGE antagonist, was administered as a single intraperitoneal injection immediately after reperfusion. Total infarct volume, neurological severity, and mechanistic analyses were compared between vehicle and azeliragon groups. The 9.4 T animal magnetic resonance imaging analysis demonstrated that total infarct volume was significantly lower in the azeliragon group compared with the vehicle group (125.3 ± 26.2 mm³ vs. 240.5 ± 21.6 mm³; p = 0.003). Additionally, the modified neurological severity scores were significantly lower in the azeliragon group compared with the vehicle group (6.4 ± 1.7 vs. 11.1 ± 0.7; p = 0.012). The neuroprotective effect was consistently observed in a 4-day hyperglycemic model. Mechanistic analyses, including immunohistochemistry and Western blotting, revealed that azeliragon treatment significantly reduced the levels of reactive oxygen species, apoptotic markers, and key inflammatory mediators. Specifically, the phosphorylated to total NF-κB p65 ratio was significantly lower (p = 0.030), along with the levels of tumor necrosis factor-α and interleukin-1β, in the azeliragon group compared with the vehicle group (p < 0.001 for each). Therefore, RAGE antagonism significantly reduced ischemic brain damage and neuroinflammation in diabetic cerebral ischemia, offering a promising therapeutic strategy.

糖尿病对急性缺血性脑卒中患者神经功能恶化的影响然而，快速血糖控制策略在临床试验中被证明是无效的。我们研究了靶向晚期糖基化终产物受体（RAGE）是否可以预防糖尿病性脑缺血梗死恶化。采用链脲佐菌素（50 mg/kg）腹腔注射7-8 周龄雄性Sprague-Dawley大鼠，建立糖尿病模型。糖尿病诱导后34 天短暂性大脑中动脉闭塞30分钟。Azeliragon（10 mg/kg）是一种RAGE拮抗剂，在再灌注后立即单次腹腔注射。总梗死面积、神经系统严重程度和机制分析比较了两组间的差异。9.4 T动物磁共振成像分析表明,梗塞总量显著低于azeliragon组相比,车辆组(125.3 ±26.2  mm3 vs 240.5 ±21.6  mm3; p = 0.003)。此外，与载药组相比，杜鹃花组改良神经系统严重程度评分显著降低（6.4 ± 1.7 vs 11.1 ± 0.7;p = 0.012）。在为期4天的高血糖模型中持续观察到神经保护作用。机制分析，包括免疫组织化学和Western blotting，显示azelagon治疗显著降低活性氧、凋亡标志物和关键炎症介质的水平。具体而言，与载药组相比，鸢尾素组磷酸化的NF-κB p65与总NF-κB p65之比显著降低（p = 0.030），肿瘤坏死因子-α和白细胞介素-1β水平也显著降低（p . 0.05）

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引用次数: 0

Molecular regulation of exercise training on hippocampal neuroprotection in post-traumatic brain injury: A systematic review 运动训练对创伤后脑损伤海马神经保护的分子调控：系统综述。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-03-01 Epub Date: 2025-12-06 DOI: 10.1016/j.expneurol.2025.115587

Farhan Yousaf , Sean Kao , Shahid Ishaq , Shin-Da Lee

Objective

Traumatic brain injury (TBI) induces oxidative stress, neuroinflammation, programmed cell death, mitochondrial dysfunction, impaired neurotrophic signaling, and neurogenesis, contributing to hippocampal dysfunction. Exercise training is a promising non-pharmacological intervention with potential neuroprotective effects. This systematic review aimed to evaluate the effectiveness of exercise training on the neurobiological mechanisms and cognitive function post-TBI.

Methods

PubMed, Embase, and Web of Science were searched up to July 2025, following the PRISMA 2020 guidelines. Of 1855 records, 44 studies involving post-TBI animals and exercise training as intervention were included. Exercise protocols varied, including voluntary wheel running, treadmill running, and swimming, with durations ranging from 7 to 94 days, and 4–7 sessions per week. The quality of included studies was appraised on the CAMARADES checklist.

Results

Exercise training reduced hippocampal reactive oxygen species (ROS), microglial reactivity, pro-inflammatory cytokines, and caspase-3 activity, while increasing total antioxidant capacity (TAC) and anti-apoptotic markers in post-TBI rodents. It elevated PGC-1α, electron transport system activity, BDNF, TrkB, and Synapsin-1 expression, and promoted neurogenesis post-TBI. Functionally, exercise improved cognitive function, spatial learning, and memory, and reduced anxiety and depression-like behaviors in post-TBI rodents.

Conclusion

Exercise training reduced oxidative stress, neuroinflammation, apoptosis, and enhanced mitochondrial function, neurotrophic signaling, neurogenesis, and cognitive function in post-TBI rodents. (PROSPERO: CRD420251072276).

目的：创伤性脑损伤（TBI）诱导氧化应激、神经炎症、程序性细胞死亡、线粒体功能障碍、神经营养信号和神经发生受损，导致海马功能障碍。运动训练是一种很有前途的非药物干预，具有潜在的神经保护作用。本系统综述旨在评价运动训练对脑损伤后神经生物学机制和认知功能的影响。方法：按照PRISMA 2020指南，检索截至2025年7月的PubMed、Embase和Web of Science。在1855项记录中，有44项研究涉及脑外伤后动物和运动训练作为干预。锻炼方案多种多样，包括自主轮跑、跑步机跑和游泳，持续时间从7到94 天不等，每周4-7次。纳入研究的质量用CAMARADES检查表进行评价。结果：运动训练降低了脑外伤后啮齿动物海马活性氧（ROS）、小胶质细胞反应性、促炎细胞因子和caspase-3活性，同时增加了总抗氧化能力（TAC）和抗凋亡标志物。上调PGC-1α、电子传递系统活性、BDNF、TrkB和Synapsin-1表达，促进脑外伤后神经发生。在功能上，运动改善了脑外伤后啮齿动物的认知功能、空间学习和记忆，并减少了焦虑和抑郁样行为。结论：运动训练可降低脑外伤后啮齿动物的氧化应激、神经炎症、细胞凋亡，增强线粒体功能、神经营养信号、神经发生和认知功能。(普洛斯彼罗:CRD420251072276)。

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引用次数: 0

Excitation–inhibition imbalance as a common thread linking early Alzheimer's disease with temporal lobe epilepsy 兴奋-抑制失衡是早期阿尔茨海默病与颞叶癫痫之间的共同线索。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-03-01 Epub Date: 2025-11-29 DOI: 10.1016/j.expneurol.2025.115581

Nwife Getrude Okechukwu , Claudio Zaccone , Livia La Barbera , Annalisa Nobili , Marcello D'Amelio

Growing evidence suggests that network hyperexcitability is a pivotal yet under-recognized pathology linking early Alzheimer's disease (AD) with mesial Temporal Lobe Epilepsy (mTLE). This narrative review synthesises pre-clinical and clinical data showing how disruption of excitation–inhibition balance, driven chiefly by the loss or dysfunction of parvalbumin- and somatostatin-positive GABAergic interneurons (INs), emerges early in AD and fosters subclinical epileptiform activity that hastens cognitive decline. We integrate findings that degeneration of Ventral Tegmental Area dopaminergic projections further destabilises hippocampal circuits by diminishing D2-mediated restraint of pyramidal firing and attenuating anti-inflammatory signalling. Convergent co-pathologies, soluble amyloid-β oligomers, tau mis-localisation, glutamate-dependent excitotoxicity and glia-mediated neuroinflammation amplify IN vulnerability and form a self-reinforcing loop of hyperexcitability, plasticity failure and neurodegeneration. Parallels with mTLE, where similar IN and dopaminergic deficits precipitate seizures, provide a mechanistic framework for interpreting EEG abnormalities and seizure susceptibility in prodromal AD. We critically appraise the therapeutic potential of interventions that restore excitation–inhibition balance or neuromodulatory tone, including interneuron-sparing agents, selective D2-like agonists, transcranial stimulation and anti-inflammatory or anti-excitotoxic strategies. By viewing early AD through a circuit-centric lens that bridges neurodegeneration and Epilepsy, we highlight testable biomarkers, propose stage-specific targets and argue that timely suppression of hyperexcitability could slow progression far upstream of irreversible neuronal loss. Such precision approaches may redefine disease modification by stabilizing vulnerable hippocampal networks before cognitive function is irrevocably compromised.

越来越多的证据表明，网络高兴奋性是早期阿尔茨海默病（AD）与中颞叶癫痫（mTLE）之间的关键病理，但尚未得到充分认识。这篇叙述性综述综合了临床前和临床数据，显示了主要由小白蛋白和生长抑素阳性gaba能中间神经元（INs）的丢失或功能障碍所驱动的兴奋-抑制平衡的破坏是如何在AD早期出现的，并促进了亚临床癫痫样活动，加速了认知能力的下降。我们整合了腹侧被盖区多巴胺能投射的退化通过减少d2介导的锥体放电抑制和减弱抗炎信号进一步破坏海马回路的稳定。会聚性共病理、可溶性淀粉样蛋白-β低聚物、tau蛋白错定位、谷氨酸依赖的兴奋性毒性和胶质细胞介导的神经炎症放大了IN易感性，形成了一个自我强化的超兴奋性、可塑性衰竭和神经退行性循环。与mTLE相似的是，类似的IN和多巴胺能缺陷会导致癫痫发作，这为解释前驱AD的脑电图异常和癫痫易感性提供了机制框架。我们批判性地评估了恢复兴奋-抑制平衡或神经调节张力的干预措施的治疗潜力，包括神经元间保留剂、选择性d2样激动剂、经颅刺激和抗炎或抗兴奋毒性策略。通过连接神经变性和癫痫的电路中心透镜观察早期AD，我们强调了可测试的生物标志物，提出了特定阶段的靶点，并认为及时抑制高兴奋性可以减缓不可逆神经元丧失的上游进展。这种精确的方法可以在认知功能不可逆转地受损之前稳定脆弱的海马体网络，从而重新定义疾病治疗。

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引用次数: 0

Axon guidance deficits in a human sensory-like neuron model of Fabry disease 法布里病人类感觉神经元模型中的轴突引导缺陷。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-03-01 Epub Date: 2025-11-20 DOI: 10.1016/j.expneurol.2025.115564

Christoph Erbacher , Aneeta Andrews , Till Sauerwein , Maximilian Breyer , Panagiota Arampatzi , Maximilian Koch , Stephanie Lamer , Tom Gräfenhan , Andreas Schlosser , Nurcan Üçeyler

Fabry disease (FD) is a rare genetic galactosidase alpha (GLA) gene associated lysosomal disorder caused by alpha-galactosidase A (AGAL) deficiency, leading to sphingolipid (globotriaosylceramide, Gb3) accumulation in multiple tissues. Burning pain due to small fiber neuropathy is an early symptom with great impact on health-related quality of life. The pathophysiological role of Gb3 accumulations in sensory neurons of the dorsal root ganglia is incompletely understood. We have differentiated induced pluripotent stem cells of an isogenic GLA knockout line (p.S364del, hemizygous) and its healthy control into sensory-like neurons to model FD in vitro. We have compared both lines on transcriptional and proteomic level and investigated the effects of AGAL enzyme supplementation. FD sensory neurons showed dysregulation of disease-related pathways, including axon guidance at both RNA and protein level and microfluidic assays revealed shorter neurite length. While AGAL did not restore the transcriptomic state, it reduced Gb3 accumulation and lowered protein ephrin 5 A and glycoprotein M6A level. These findings highlight axon guidance alterations in an isogenic human FD sensory neuron model, with potential implications for early central and peripheral innervation in small fiber neuropathy.

法布里病（FD）是一种罕见的遗传性半乳糖苷酶α (GLA)基因相关溶酶体疾病，由α -半乳糖苷酶a （AGAL）缺乏引起，导致鞘脂（globotriaosylceramide, Gb3）在多组织积累。小纤维神经病变引起的烧灼痛是一种早期症状，对健康相关的生活质量有很大影响。背根神经节感觉神经元中Gb3积累的病理生理作用尚不完全清楚。我们将一种等基因GLA敲除系（p.S364del，半合子）及其健康对照的诱导多能干细胞分化为感觉神经元，以体外模拟FD。我们比较了两种品种的转录和蛋白质组学水平，并研究了补充AGAL酶的影响。FD感觉神经元显示疾病相关通路失调，包括RNA和蛋白质水平的轴突引导，微流体实验显示神经突长度较短。虽然AGAL没有恢复转录组状态，但它减少了Gb3的积累，降低了蛋白ephrin 5 A和糖蛋白M6A水平。这些发现强调了等基因人类FD感觉模型中轴突引导的改变，对小纤维神经病的早期中枢和外周神经支配有潜在的影响。

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引用次数: 0

The phenotypic transformation of astrocytes after AIS can be regulated by microglial GSDMD-mediated pyroptosis AIS后星形胶质细胞的表型转化可受gsdmd介导的小胶质细胞热凋亡的调控。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-03-01 Epub Date: 2025-12-11 DOI: 10.1016/j.expneurol.2025.115595

Yige Zhang , Yifang Zhou , Wan Zhang , Yiwei Qian , Zixin Chen , Lulu Pei , Ding Zhang , Wanxuan Cheng , Mengke Tian , Ce Zong , Xin Wang , Yamin Wang , Jiaxin Wang , MingMing Ning , Jun Tan , Zongping Xia , Yuming Xu , Yuan Cao , Bo Song

Background

Microglial pyroptosis contributes to the pathogenesis of ischemic stroke through multiple pathways. However, it is unclear how it contributes to the phenotype switching of neuroinflammatory/ neuroprotective astrocytes.

Methods

This study established a mouse MCAO model and utilized microglial Gsdmd gene knockout mice to examine neuroinflammatory/neuroprotective astrocyte-related protein expression, infarct volume, mNSS scores, and other metrics. Additionally, a transwell co-culture model of microglia and astrocytes was constructed, followed by treatment with IL-1β, pyroptosis inhibitor DSF, and IL-1R1 inhibitor IL-1RA.

Results

The findings confirm that microglial GSDMD protein-mediated pyroptosis influences the phenotypic transformation of neuroinflammatory/neuroprotective astrocytes. Specifically, GSDMD-mediated pyroptosis in microglia releases IL-1β, which binds to the IL-1R1 receptor, reversing neuroinflammatory / neuroprotective astrocyte polarization.

Conclusion

This mechanism improves AIS prognosis and may serve as a promising therapeutic candidate in AIS.

背景：小胶质细胞焦亡通过多种途径参与缺血性卒中的发病机制。然而，尚不清楚它如何促进神经炎性/神经保护性星形胶质细胞的表型转换。方法：本研究建立小鼠MCAO模型，利用小胶质Gsdmd基因敲除小鼠检测神经炎症/神经保护星形胶质细胞相关蛋白表达、梗死体积、mNSS评分等指标。建立小胶质细胞和星形胶质细胞的transwell共培养模型，然后用IL-1β、焦腐抑制剂DSF和IL-1R1抑制剂IL-1RA处理。结果：证实小胶质细胞GSDMD蛋白介导的焦亡影响神经炎性/神经保护性星形胶质细胞的表型转化。具体来说，gsdmd介导的小胶质细胞焦亡释放IL-1β， IL-1β与IL-1R1受体结合，逆转神经炎症/神经保护星形胶质细胞极化。结论：该机制改善了AIS的预后，可能是治疗AIS的有希望的候选药物。

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引用次数: 0

Amelioration of transcriptional disturbances in female BACHD rats by environmental enrichment 环境富集改善雌性BACHD大鼠转录紊乱。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-03-01 Epub Date: 2025-11-17 DOI: 10.1016/j.expneurol.2025.115561

A. Kilzheimer , T. Hentrich , A. Novati , H. Nguyen , Z. Wassouf , J.M. Schulze-Hentrich

Huntington's disease is a devastating neuropsychiatric hereditary illness. While progressive in nature, there is evidence suggesting the disease can be positively modified through lifestyle changes. The influence of putative protective factors can be modelled in animal models by enriched environments. As of today, there is a wide array of different implementations of environmental enrichment with little comparative information regarding their respective effects. Aiming to better understand the connection between environmental stimulation and disease progression, we examined behavioural and striatal gene expression changes in female BACHD transgenic rats exposed to either a standard environment or one of two environmental enrichment protocols differing in temporal onset. Our results show striking transgenic effects on phenotype and gene expression. Both glial and neuronal functions and cellular pathways were affected. When exposed to environmental enrichment, both protocols markedly reduced striatal dysregulation, yet some differences were observed between the two designs, thus inviting future studies to further examine the differential effects of specific paradigms. Our findings highlight the promising potential of lifestyle interventions to lighten disease burden of patients and improving their quality of life.

亨廷顿舞蹈症是一种毁灭性的神经精神遗传性疾病。虽然这种疾病本质上是渐进的，但有证据表明，这种疾病可以通过改变生活方式得到积极的改善。假定的保护因素的影响可以通过丰富的环境在动物模型中模拟。到目前为止，有各种各样不同的环境富集实施方法，但很少有关于其各自影响的比较资料。为了更好地了解环境刺激与疾病进展之间的联系，我们研究了暴露于标准环境或两种不同时间开始的环境浓缩版本之一的雌性BACHD转基因大鼠的行为和纹状体基因表达变化。我们的研究结果显示转基因对表型和基因表达有显著的影响。胶质和神经元功能以及细胞通路均受到影响。当暴露于环境富集时，每种变异都显着减少纹状体失调，但在两种设计之间观察到一些差异，因此需要进一步研究特定范式的差异效应。我们的研究结果强调了生活方式干预在减轻患者疾病负担和改善其生活质量方面的巨大潜力。

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引用次数: 0

Alpha 7 nicotinic acetylcholine receptor contributes to long-term cognitive recovery following ischemic stroke α - 7烟碱乙酰胆碱受体对缺血性脑卒中后长期认知恢复的影响。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-03-01 Epub Date: 2025-11-19 DOI: 10.1016/j.expneurol.2025.115562

Dustin T. Nguyen , Kate Mendoza , Cassandra Hall, Chunfeng Tan, Anjali Chauhan

Stroke is associated with autonomic dysfunction and reduced acetylcholine (ACh), a neurotransmitter critical for cognition. ACh signals in part through the alpha-7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel involved in synaptic plasticity, learning, and memory. Impaired α7nAChR signaling has been linked to heightened neuroinflammation and poor acute stroke recovery. Here, we investigated whether α7nAChR contributes to post-stroke cognitive recovery in young male mice. Wild-type (WT) and α7nAChR knockout (α7n⁰KO) mice underwent 60-min middle cerebral artery occlusion (MCAO). In a pharmacology cohort, the α7nAChR agonist GTS-21 was administered immediately after reperfusion and then daily for 20 days. Cognitive performance was assessed by novel object recognition (day 10), object location (day 20), and Barnes maze and open field testing (day 28). Mass spectrometry at 24 h quantified brain ACh. Flow cytometry at 24 h, 7 days, and 30 days measured microglial and brain F4/80 macrophages. Immunohistochemistry at day 30 evaluated gliosis and neurogenesis. WT mice showed reduced ipsilateral ACh and α7nAChR⁺ microglia with increased TNF-α versus sham. Compared with WT, α7n⁰KO mice exhibited greater myeloid infiltration at 24 h, fewer IL-6⁺microglia and F4/80⁺macrophages with impaired STAT3/SOCS3 signaling at day 7, and by day 30, reduced reparative microglia, fewer F4/80⁺ macrophages, greater tissue loss, demyelination, gliosis, reduced SVZ neurogenesis, and impaired cognitive recovery. GTS-21 treatment improved cognition and reduced gliosis, supporting a protective role for α7nAChR activation. In conclusion, α7nAChR signaling supports reparative immune programs and promotes neurorepair after stroke, thereby enhancing long-term cognitive recovery.

中风与自主神经功能障碍和乙酰胆碱（一种对认知至关重要的神经递质）减少有关。乙酰胆碱部分通过α -7烟碱乙酰胆碱受体（α7nAChR）传递信号，α -7烟碱乙酰胆碱受体是一种参与突触可塑性、学习和记忆的配体门控离子通道。α7nAChR信号受损与神经炎症加剧和急性卒中恢复不良有关。在这里，我们研究α7nAChR是否有助于年轻雄性小鼠中风后的认知恢复。野生型（WT）和α7nAChR敲除（α7n0KO）小鼠进行60分钟的大脑中动脉闭塞（MCAO）。在药理学队列中，α7nAChR激动剂GTS-21在再灌注后立即给予，然后每天给予20 天。通过新物体识别（第10天）、物体定位（第20天）和巴恩斯迷宫和开放场地测试（第28天）评估认知表现。24 h质谱法定量脑乙酰胆碱。流式细胞术在24 h、7 天和30 天测量小胶质细胞和脑F4/80巨噬细胞。第30天免疫组化评价胶质瘤和神经发生。与假手术相比，WT小鼠显示同侧ACh和α7nAChR+小胶质细胞减少，TNF-α增加。与WT相比，α7n0KO小鼠在24 h时骨髓浸润增加，第7天STAT3/SOCS3信号受损的IL-6+小胶质细胞和F4/80+巨噬细胞减少，到第30天，修复性小胶质细胞减少，F4/80+巨噬细胞减少，组织丢失，脱髓鞘，胶质瘤，SVZ神经发生减少，认知恢复受损。GTS-21治疗可改善认知并减少胶质瘤，支持α7nAChR激活的保护作用。综上所述，α7nAChR信号支持脑卒中后的修复性免疫程序，促进神经修复，从而促进长期认知恢复。

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引用次数: 0

miR-15b-5p impairs myelin repair and cognitive recovery after ischemic stroke by targeting the E2F7/CXCL2 axis miR-15b-5p通过靶向E2F7/CXCL2轴损害缺血性卒中后髓磷脂修复和认知恢复。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-03-01 Epub Date: 2025-12-14 DOI: 10.1016/j.expneurol.2025.115589

Yizhen Weng , Jialei Zhou , Lulu Zhang , Xinyi He , Hui Guo , Quanquan Zhang , Haiying Li , Xiang Tang , Xiang Li Sr

Ischemic stroke often causes demyelination and cognitive impairment. Emerging evidence suggests that microRNAs regulate gene expression and influence myelin repair and cognitive recovery after stroke. Here, transcriptomic analysis and RT-qPCR validation revealed marked upregulation of miR-15b-5p expression in the hippocampal regions of MCAO/R rats. Similarly, elevated serum miR-15b-5p levels were observed in stroke patients and positively correlated with NIHSS scores and infarct volumes. Functional studies involving intracerebroventricular administration of miR-15b-5p agomirs or antagomirs revealed that inhibition of miR-15b-5p markedly enhanced cognitive performance and facilitated myelin repair, as demonstrated by immunofluorescence and transmission electron microscopy. In contrast, overexpression of miR-15b-5p through agomir administration aggravated cognitive impairments and demyelination. Mechanistically, E2F7 was identified as a direct target of miR-15b-5p via dual-luciferase reporter assays. Suppression of E2F7 led to increased expression of the pro-inflammatory chemokine CXCL2, thereby exacerbating neuroinflammation and demyelination. In contrast, inhibition of miR-15b-5p restored E2F7 expression and significantly reduced CXCL2 levels, as confirmed by Western blotting and enzyme-linked immunosorbent assay. Collectively, these findings reveal a novel miR-15b–E2F7–CXCL2 axis that modulates myelin repair and cognitive recovery after ischemic stroke, highlighting miR-15b-5p as a potential therapeutic target.

缺血性中风常引起脱髓鞘和认知障碍。新出现的证据表明，microRNAs调节基因表达并影响脑卒中后髓磷脂修复和认知恢复。本研究中，转录组学分析和RT-qPCR验证显示MCAO/R大鼠海马区miR-15b-5p表达显著上调。同样，脑卒中患者血清miR-15b-5p水平升高，且与NIHSS评分和梗死体积呈正相关。脑室内给予miR-15b-5p阿戈米或安塔戈米的功能研究显示，免疫荧光和透射电镜显示，抑制miR-15b-5p显着增强认知能力并促进髓磷脂修复。相反，通过阿戈米尔过表达miR-15b-5p加重了认知障碍和脱髓鞘。在机制上，通过双荧光素酶报告基因检测，E2F7被确定为miR-15b-5p的直接靶标。抑制E2F7导致促炎趋化因子CXCL2的表达增加，从而加剧神经炎症和脱髓鞘。相比之下，经Western blotting和酶联免疫吸附试验证实，抑制miR-15b-5p可恢复E2F7表达并显著降低CXCL2水平。总的来说，这些发现揭示了一种新的miR-15b-E2F7-CXCL2轴，它调节缺血性卒中后髓磷脂修复和认知恢复，突出了miR-15b-5p作为潜在的治疗靶点。

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引用次数: 0

Meprin β elevates hippocampal soluble Aβ in the APP/V717I mouse model Meprin β在APP/V717I小鼠模型中升高海马可溶性Aβ。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-03-01 Epub Date: 2025-12-19 DOI: 10.1016/j.expneurol.2025.115600

Maximilian Keller , Celine Gallagher , Liana Marengo , Kira Bickenbach , Ulrich Schmitt , Mohammad Abukhalaf , Andreas Tholey , Simon Kreiselmaier , Christoph Becker-Pauly , Thomas Mittmann , Claus U. Pietrzik

The emergence of Alzheimer's disease (AD) pathology has been the focus of multiple hypotheses, with amyloid β (Aβ) playing a central role due to its presence in both familial and sporadic AD. Therefore, a crucial aspect of AD research is understanding the generation of different Aβ species. Aβ peptides result from the proteolytic processing of Amyloid Precursor Protein (APP) by β- and γ-secretases, with BACE1 being the most prominent β-secretase. However, BACE1-overexpressing mouse models exhibit disadvantages, making them limited for AD research. Importantly, N-terminally truncated Aβ species, which constitute up to 70 % of Aβ in AD brains, are not generated by BACE1. In recent years, alternative proteases capable of cleaving APP have been identified, bridging the gap between N-terminally truncated Aβ species and BACE1-derived Aβ. Among these novel players, the metalloprotease meprin β has emerged as a risk factor in AD pathology, generating both N-terminally truncated and full-length Aβ species. Our primary objective was to develop a mouse model that more accurately resembles the pathology of AD beyond BACE1-overexpressing models, while simultaneously confirming APP cleavage of meprin β in the hippocampus and cerebral cortex. Overexpression of meprin β led to a marked increase in soluble Aβ levels, particularly in the hippocampus, indicating a higher vulnerability or elevated meprin β activity in this region compared to the cerebral cortex. Notably, this biochemical change occurred without any observable behavioral deficits, suggesting a region-specific role of meprin β in AD pathology that may extend beyond immediate functional impairment.

阿尔茨海默病（AD）病理的出现一直是多种假设的焦点，β淀粉样蛋白（a β）由于其存在于家族性和散发性AD中而起着核心作用。因此，AD研究的一个关键方面是了解不同a β物种的产生。β肽是由β-和γ-分泌酶对淀粉样前体蛋白（APP）进行蛋白水解而产生的，其中BACE1是最重要的β-分泌酶。然而，bace1过表达的小鼠模型有其缺点，限制了其在AD研究中的应用。重要的是，在AD大脑中占70% %的n端截断的Aβ物种不是由BACE1产生的。近年来，已经发现了能够切割APP的替代蛋白酶，弥补了n端截断的Aβ物种与bace1衍生的Aβ之间的差距。在这些新的参与者中，金属蛋白酶meprin β已经成为AD病理的一个危险因素，产生n端截断和全长a β种。我们的主要目标是建立一种比bace1过表达模型更准确地接近AD病理的小鼠模型，同时确认海马和大脑皮层中meprin β的APP切割。meprin β的过度表达导致可溶性a β水平显著增加，特别是在海马体中，这表明与大脑皮层相比，该区域的meprin β活性更高。值得注意的是，这种生化变化发生时没有任何可观察到的行为缺陷，这表明meprin β在AD病理中的区域特异性作用可能超出了直接的功能损伤。

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引用次数: 0

A new microinfarcts model produces widespread bilateral infarcts and persistent cognitive deficits in middle-aged mice 一种新的微梗死模型在中年小鼠中产生广泛的双侧梗死和持续的认知缺陷。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-03-01 Epub Date: 2025-12-16 DOI: 10.1016/j.expneurol.2025.115598

Zhongwu Liu , Mikkala Mccann , Brianna Powell , Julie Landschoot-Ward , Zheng Gang Zhang , Michael Chopp

Background

Multi-infarct dementia (MID), a severe form of vascular cognitive impairment, results from cumulative impact of multiple cerebral microinfarcts (MMIs). Current preclinical models primarily rely on unilateral induction of MMIs, which fails to reproduce bilateral lesion distribution and persistent cognitive decline characteristic of human disease.

Objective

To develop and characterize a modified bilateral MMI model that more accurately reflects the clinical and pathological features of MID.

Methods

Twelve-month-old male C57BL/6J mice underwent either unilateral or bilateral MMI induction by microsphere embolization via the internal carotid artery. Bilateral induction was achieved by transiently occluding the contralateral common carotid artery during microsphere infusion. Behavioral assessments using novel object recognition (NOR) and elevated plus maze (EPM) were conducted on days 7, 14, and 28 post-surgery. Histological Hematoxylin and Eosin staining and immunohistochemical analyses using antibodies against Iba1 and GFAP were performed to evaluate lesion distribution and neuroinflammation.

Results

The modified bilateral procedure successfully induced widespread infarcts across both hemispheres. Bilateral MMI mice exhibited significantly greater and persistent cognitive impairment, demonstrated by a reduced NOR discrimination index and decreased open-arm exploration in the EPM persisting through day 28, than did unilateral MMI mice. Histological analysis confirmed bilateral microinfarcts and significant increase in Iba1- and GFAP-positive staining, indicating robust and sustained bilateral neuroinflammation.

Conclusion

This modified bilateral MMI procedure reproduces key pathological and functional features of human MID, overcoming the limitations of traditional unilateral models. The new model provides a clinically relevant platform for investigating mechanisms underlying vascular cognitive impairment and evaluating potential disease-modifying therapies.

背景：多发性脑梗死性痴呆（MID）是一种严重的血管性认知障碍，由多发性脑微梗死（mmi）的累积影响引起。目前的临床前模型主要依赖于单侧诱导mmi，无法再现人类疾病特征的双侧病变分布和持续认知能力下降。方法：12月龄雄性C57BL/6J小鼠经颈内动脉微球栓塞诱导单侧或双侧MMI。双侧诱导是通过微球输注期间短暂闭塞对侧颈总动脉实现的。术后第7、14和28天分别采用新目标识别（NOR）和升高+迷宫（EPM）进行行为评估。组织苏木精染色和伊红染色，免疫组化分析抗Iba1和GFAP抗体，以评估病变分布和神经炎症。结果：改良的双侧手术成功地诱导了两脑半球广泛的梗死。与单侧MMI小鼠相比，双侧MMI小鼠表现出更大且持续的认知障碍，这表现在持续28天的EPM中NOR辨别指数降低和张开臂探索减少。组织学分析证实双侧微梗死，Iba1和gfap阳性染色显著增加，表明双侧神经炎症强劲且持续。结论：这种改良的双侧MMI手术再现了人类MID的关键病理和功能特征，克服了传统单侧模型的局限性。新模型为研究血管性认知障碍的机制和评估潜在的疾病改善疗法提供了一个临床相关的平台。

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引用次数: 0