Neurochemistry international最新文献_第3页

Investigating the role of GABAergic interneurons in the antidepressant-like mechanism of agomelatine gaba能中间神经元在阿戈美拉汀抗抑郁机制中的作用

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2026-01-01 Epub Date: 2025-12-09 DOI: 10.1016/j.neuint.2025.106101

Suhong Ye , Qiaolu Xu , Nashwa Amin , Ling Bao , Yang Yang , Irum Naz Abbasi , Marong Fang

Depression is a prevalent and debilitating mental disorder with substantial impacts on global health and socioeconomic costs. Despite various antidepressants targeting monoaminergic neurotransmission, a significant proportion of patients fail to achieve remission with existing treatments. Agomelatine (AGO), as a novel antidepressant, has shown promise in treating depression. However, the neural circuits and molecular mechanisms underlying its therapeutic effects remain largely unknown. This study aimed to investigate the role of GABAergic neural circuits on the antidepressant effects of AGO and elucidate the underlying cellular and molecular mechanisms. A chronic unpredictable mild stress (CUMS) mouse model was used to induce depressive-like behaviors. Genetic manipulation was employed to selectively ablate GABAergic neurons, and the effects of AGO treatment on behavioral performance and neuronal morphology were assessed. Additionally, the expression of synaptic and clock genes was analyzed to explore underlying molecular mechanisms. We found that AGO treatment significantly improved the behavioral performance of CUMS mice and rescued the structural integrity and quantity of central neurons. It regulated the protein expressions of VGAT, VGLUT1, and Gad65 in the brain tissues of CUMS mice. Notably, AGO altered the protein and gene expressions in GABAergic neural circuits across different brain regions. Morphological analysis revealed that AGO improved dendritic spine density and length in neurons in the selective ablation of GABAergic interneurons. The antidepressant effects of AGO involve the modulation of GABAergic neural circuits as a critical but non-exclusive target, alongside the restoration of GABAergic-glutamatergic balance, synaptic function, and clock gene expressions. These findings highlight AGO's potential in normalizing disrupted neuronal function in depression and offer insights into novel multi-target therapeutic strategies.

抑郁症是一种普遍存在的使人衰弱的精神障碍，对全球健康和社会经济成本产生重大影响。尽管有各种针对单胺能神经传递的抗抑郁药物，但很大一部分患者无法通过现有的治疗获得缓解。阿戈美拉汀（AGO）作为一种新型抗抑郁药，在治疗抑郁症方面显示出良好的前景。然而，其治疗效果背后的神经回路和分子机制在很大程度上仍然未知。本研究旨在探讨gaba能神经回路在AGO抗抑郁作用中的作用，并阐明其潜在的细胞和分子机制。采用慢性不可预测轻度应激（CUMS）小鼠模型诱导抑郁样行为。采用基因操作选择性消融gaba能神经元，评估AGO处理对行为表现和神经元形态的影响。此外，我们还分析了突触和时钟基因的表达，以探索潜在的分子机制。我们发现AGO治疗显著改善了CUMS小鼠的行为表现，恢复了中枢神经元的结构完整性和数量。调节CUMS小鼠脑组织中VGAT、VGLUT1、Gad65蛋白的表达。值得注意的是，AGO改变了gaba能神经回路中不同脑区的蛋白质和基因表达。形态学分析显示，在选择性消融gaba能中间神经元时，AGO可改善神经元的树突棘密度和长度。AGO的抗抑郁作用包括gaba能神经回路的调节，这是一个关键但非排他的目标，同时还包括gaba能-谷氨酸能平衡、突触功能和时钟基因表达的恢复。这些发现突出了AGO在使抑郁症中受损的神经元功能正常化方面的潜力，并为新的多靶点治疗策略提供了见解。

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引用次数: 0

Assessing the critical role of ceramide in the pathogenesis of Alzheimer's disease and its clinical significance 神经酰胺在阿尔茨海默病发病机制中的关键作用及其临床意义。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2026-01-01 Epub Date: 2025-12-14 DOI: 10.1016/j.neuint.2025.106104

Yi-Wen Huang , Hua-Chen Chan , Jing-Yi Khoo , Mei-Lin Chan , Daniel Bender , Vinoth Kumar Ponnusamy , Abdel Ali Belaidi , Liang-Yin Ke

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, and synaptic loss. Emerging evidence indicates that apolipoprotein E (APOE) polymorphism and dysregulated ceramide metabolism are critical links among these pathogenic processes. Ceramide accumulation in the brain contributes to Aβ generation, tau phosphorylation, and neuronal apoptosis. Elevated ceramide levels have been observed in plasma, cerebrospinal fluid, and peripheral organs such as the liver, reflecting systemic lipid dysregulation. Lipoproteins—particularly low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL)—transport ceramide across the blood–brain barrier, while apoE4 isoforms exacerbate this process by disrupting vascular integrity and lipid homeostasis. In addition, hepatic and gut-derived ceramides may influence neurodegeneration through the liver–gut–brain axis. Therapeutic interventions targeting ceramide synthesis (serine palmitoyltransferase inhibitors), production (neutral sphingomyelinase inhibitors), and the ceramide/sphingosine-1-phosphate (S1P) balance show potential in preclinical models for reducing Aβ pathology, tau aggregation, and neuroinflammation. These findings position ceramide metabolism as a critical mediator of AD pathogenesis and a promising target for diagnosis and treatment. Modulating ceramide and S1P signaling could complement current amyloid- and tau-directed therapies, offering new opportunities for disease modification and early intervention.

阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是淀粉样蛋白-β (a β)沉积、tau过度磷酸化和突触丧失。新出现的证据表明载脂蛋白E （APOE）多态性和神经酰胺代谢失调是这些致病过程的关键环节。神经酰胺在大脑中的积累有助于Aβ的产生，tau磷酸化和神经元凋亡。在血浆、脑脊液和肝等外周器官中观察到神经酰胺水平升高，反映了全身性脂质失调。脂蛋白——尤其是低密度脂蛋白（LDL）和极低密度脂蛋白（VLDL）——通过血脑屏障运输神经酰胺，而apoE4亚型通过破坏血管完整性和脂质稳态加剧了这一过程。此外，肝和肠源性神经酰胺可能通过肝-肠-脑轴影响神经退行性变。针对神经酰胺合成（丝氨酸棕榈酰基转移酶抑制剂）、产生（中性鞘磷脂酶抑制剂）和神经酰胺/鞘磷脂-1-磷酸（S1P）平衡的治疗干预在临床前模型中显示出减少Aβ病理、tau聚集和神经炎症的潜力。这些发现表明神经酰胺代谢是阿尔茨海默病发病机制的关键介质，也是诊断和治疗的一个有希望的靶点。调节神经酰胺和S1P信号可以补充目前的淀粉样蛋白和tau定向治疗，为疾病改变和早期干预提供新的机会。

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引用次数: 0

GPR55 deficiency exacerbates cognitive impairments and Alzheimer's disease-like pathology in mice GPR55缺乏会加剧小鼠的认知障碍和阿尔茨海默病样病理。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2026-01-01 Epub Date: 2025-12-15 DOI: 10.1016/j.neuint.2025.106105

Bing Fan , YuSheng Liang , TianTian Zhi , Lei Wu , YangXia Wu , Yan Yang , Zhi Xie , Xian Wu

Background

Alzheimer's disease (AD) is the most common type of dementia, characterized by progressive cognitive decline and neuronal damage. Although studies have indicated a link between G-protein coupled receptor 55 (GPR55) and AD-related cognitive impairment, the underlying mechanisms remain unclear. Here, we aim to further investigate the role of GPR55 in the pathogenesis of AD.

Methods

We used viral vectors to knock down GPR55 expression in the hippocampus of normal mice. We also generated GPR55 knockout in AD mice by crossing GPR55^−/− mice with APP/PS1 transgenic mice (APP/PS1; GPR55^−/−). Behavioral tests were conducted to assess spatial memory deficits in 9-month-old APP/PS1; GPR55^−/− mice. We also assessed the amyloid β (Aβ) deposition, glial cell activation, and synaptic protein expression in the hippocampus. In addition, we used AAV9 viruses to overexpress GPR55 in the hippocampus of APP/PS1; GPR55^−/− mice to further observe its effect on cognitive function.

Results

Knockdown of GPR55 in the hippocampus induces AD-like pathology, cognitive dysfunction, neuroinflammation, and synaptic plasticity damage in normal mice. This was evidenced by increased hippocampal levels of Aβ and p-Tau, enhanced glial cell activation accompanied by upregulation of proinflammatory cytokines, and aggravated synaptic plasticity damage in the normal mice. Furthermore, knockdown of GPR55 induced the reduction of P-AKT1/2/3/AKT1/2/3 and P-GSK3β/GSK3β, while increasing the expression of P-ERK1/2/ERK1/2 in the hippocampus of normal mice. In addition, GPR55 deficiency exacerbated AD-like pathology and spatial learning and memory deficits in APP/PS1 mice. Conversely, AAV9-mediated overexpression of GPR55 rescued spatial memory impairments in APP/PS1; GPR55^−/− mice.

Conclusions

These findings underscore the critical role of GPR55 in AD progression and highlight its potential as a therapeutic target for AD treatment.

背景：阿尔茨海默病（AD）是最常见的痴呆症类型，以进行性认知能力下降和神经元损伤为特征。虽然研究表明g蛋白偶联受体55 （GPR55）与ad相关的认知障碍之间存在联系，但其潜在机制尚不清楚。在此，我们旨在进一步研究GPR55在AD发病机制中的作用。方法：采用病毒载体敲低正常小鼠海马组织中GPR55的表达。我们还通过将GPR55-/-小鼠与APP/PS1转基因小鼠（APP/PS1; GPR55-/-）杂交，在AD小鼠中实现了GPR55基因敲除。应用行为测试评估9月龄APP/PS1患儿空间记忆缺陷；GPR55 - / -小鼠。我们还评估了海马中β淀粉样蛋白（Aβ）沉积、胶质细胞活化和突触蛋白表达。此外，我们利用AAV9病毒在APP/PS1海马区过表达GPR55；进一步观察GPR55-/-对小鼠认知功能的影响。结果：正常小鼠海马GPR55表达下调可引起ad样病理、认知功能障碍、神经炎症和突触可塑性损伤。正常小鼠海马Aβ和p-Tau水平升高，胶质细胞活化增强，伴促炎细胞因子上调，突触可塑性损伤加重，均证明了这一点。此外，GPR55的下调可导致正常小鼠海马组织中P-AKT1/2/3/AKT1/2/3和P-GSK3β/GSK3β的表达减少，而P-ERK1/2/ERK1/2的表达增加。此外，GPR55缺乏加重了APP/PS1小鼠ad样病理和空间学习记忆缺陷。相反，aav9介导的GPR55过表达可挽救APP/PS1的空间记忆障碍；GPR55 - / -小鼠。结论：这些发现强调了GPR55在AD进展中的关键作用，并强调了其作为AD治疗靶点的潜力。

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引用次数: 0

SPI1 suppresses YAP phosphorylation in vascular endothelial cells to prevent intracranial aneurysm progression SPI1抑制血管内皮细胞中YAP磷酸化以防止颅内动脉瘤进展

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2026-01-01 Epub Date: 2025-12-09 DOI: 10.1016/j.neuint.2025.106100

Yikui Liu , Danyi Zheng , Lanlan Zhao , Bing Leng , Qingfang Sun , Liuguan Bian , Yongtao Zheng

This study aims to elucidate the mechanism by which YAP mediates the activity of vascular endothelial cells (ECs) in the biological process of intracranial aneurysms (IAs) and to provide a novel target for noninvasive IAs treatment. Single-nuclei RNA profiling of aneurysmal cells revealed that ECs within aneurysms exhibit an intermediate identity between arterial and venous/capillary cells, rather than clustering within the normal arterial population. These specific human ECs showed downregulated YAP expression under turbulent flow. Immunostaining of human IA tissues demonstrated reduced YAP and increased phosphorylated YAP (p-YAP) compared with superficial temporal artery walls. Using YAP-knockdown human brain microvascular endothelial cells (HBMECs), we observed elevated expression of senescence markers p21 and p16, accompanied by diminished proliferation and migration capacities. Furthermore, SPI1 (also known as PU.1) overexpression alleviated EC degeneration induced by turbulent flow through suppression of YAP phosphorylation. Collectively, our findings indicate that turbulent flow markedly reduces YAP expression while promoting its phosphorylation, thereby accelerating endothelial senescence. Importantly, SPI1 overexpression effectively mitigated turbulent-flow-induced endothelial senescence, suggesting that SPI1 may serve as a potential therapeutic target for preventing aneurysmal progression.

本研究旨在阐明YAP在颅内动脉瘤（IAs）生物学过程中介导血管内皮细胞（ECs）活性的机制，为IAs的无创治疗提供新的靶点。动脉瘤细胞的单核RNA谱显示，动脉瘤内的内皮细胞表现出动脉和静脉/毛细血管细胞之间的中间身份，而不是聚集在正常动脉群中。这些特异性的人类ECs在湍流中表现出下调的YAP表达。与颞浅动脉壁相比，人IA组织的免疫染色显示YAP减少，磷酸化YAP （p-YAP）增加。使用yap敲除的人脑微血管内皮细胞（HBMECs），我们观察到衰老标志物p21和p16的表达升高，同时增殖和迁移能力减弱。此外，SPI1（又称PU.1）过表达通过抑制YAP磷酸化减轻湍流诱导的EC变性。总的来说，我们的研究结果表明，湍流显著降低YAP的表达，同时促进其磷酸化，从而加速内皮细胞衰老。重要的是，SPI1过表达有效地减轻了湍流诱导的内皮衰老，这表明SPI1可能作为预防动脉瘤进展的潜在治疗靶点。

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引用次数: 0

ERBB4 colocalizes with phosphorylated tau aggregates in multiple tauopathies 在多种tau病变中，ERBB4与磷酸化的tau聚集物共定位

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2026-01-01 Epub Date: 2025-11-24 DOI: 10.1016/j.neuint.2025.106093

Chihiro Matsumoto , Tomohiro Kabuta , Terunori Sano , Shigeo Murayama , Yuko Saito , Yuji Takahashi

The neuregulin-ERBB4 pathway is essential for maintaining cellular function. Upon stimulation by its ligand, neuregulin, ERBB4—a receptor tyrosine kinase—triggers multiple cellular responses, including proliferation, apoptosis, differentiation, and neuromuscular junction formation. Previous research has implicated dysregulated ERBB4 signaling in the pathophysiology of several neurodegenerative disorders, such as Alzheimer's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, and Parkinson's disease. In this study, we examined ERBB4 expression in diseases characterized by phosphorylated tau (MAPT) pathology. We found that ERBB4 colocalized with neuronal and glial phosphorylated tau-positive inclusions in multiple tauopathies, including Pick's disease, Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutation. Conversely, ERBB4 did not colocalize with α-synuclein aggregates in α-synucleinopathies (Parkinson's disease and multiple system atrophy) or with neuronal intranuclear inclusions in triplet repeat disorders (Huntington's disease and dentatorubral-pallidoluysian atrophy). A co-immunoprecipitation assay indicated that ERBB4 can interact with tau intracellularly. Notably, in corticobasal degeneration, we observed ectopic ERBB4 expression in astrocytes lacking apparent phosphorylated tau aggregates. These findings suggest a potential role for ERBB4 in the pathophysiology of tau-related neurodegenerative diseases.

神经调节- erbb4通路对维持细胞功能至关重要。erbb4受体酪氨酸激酶在其配体神经调节蛋白的刺激下，引发多种细胞反应，包括增殖、凋亡、分化和神经肌肉连接形成。先前的研究表明ERBB4信号失调在一些神经退行性疾病的病理生理中，如阿尔茨海默病、进行性核上性麻痹、肌萎缩侧索硬化症和帕金森病。在这项研究中，我们检测了ERBB4在以磷酸化tau （MAPT）病理为特征的疾病中的表达。我们发现ERBB4在多种tau病变中与神经元和胶质磷酸化的tau阳性包涵体共定位，包括匹克病、阿尔茨海默病、皮质基底变性、进行性核上性麻痹、嗜阿糖颗粒病和伴有MAPT突变的额颞叶变性。相反，在α-突触核蛋白病（帕金森病和多系统萎缩）中，ERBB4不与α-突触核蛋白聚集体共定位，也不与三重重复疾病（亨廷顿病和齿状小网膜-白球萎缩）中的神经元核内包涵体共定位。免疫共沉淀法表明ERBB4可与细胞内tau蛋白相互作用。值得注意的是，在皮质基底变性中，我们在缺乏明显磷酸化tau聚集物的星形胶质细胞中观察到异位ERBB4表达。这些发现提示ERBB4在tau相关神经退行性疾病的病理生理中具有潜在的作用。

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引用次数: 0

Essential oils by name and by nature: a review of their antioxidant and neuroprotective potential in Parkinson's disease 精油的名称和性质：综述其在帕金森病中的抗氧化和神经保护潜力

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2026-01-01 Epub Date: 2025-11-24 DOI: 10.1016/j.neuint.2025.106092

Claudia Cannas , Stefano Zoroddu , Alessandra Tiziana Peana , Gaia Rocchitta , Luigi Bagella , Rossana Migheli

Oxidative stress (OS), resulting from an imbalance between reactive oxygen species (ROS) and endogenous antioxidants, plays a central role in the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). The brain's high oxygen demand and abundance of polyunsaturated fatty acids make it particularly vulnerable to ROS-induced damage. Despite major advances in research, no disease-modifying treatments for PD are currently available. Consequently, increasing attention has been directed toward natural bioactive compounds with antioxidant and neuroprotective properties. Among these, essential oils (EOs), volatile plant-derived mixtures with documented antioxidant, anti-inflammatory, and neuroactive effects, are emerging as promising adjuvants for PD management. This review critically examines the antioxidant and neuroprotective effects of well-characterized EOs evaluated in both in vitro and in vivo models of neurodegeneration. Literature searches were conducted in PubMed and Scopus up to March 2025, identifying studies investigating EOs or their major components in PD-related experimental settings. Evidence indicates that essential oils derived from the Citrus and Rosa genus, and the Lamiaceae family, can reduce intracellular ROS accumulation, inhibit lipid peroxidation, enhance endogenous antioxidant enzyme activity, and modulate both apoptotic and inflammatory pathways. These multitarget actions are often attributed to synergistic interactions among EO constituents, such as limonene, linalool, thymol, and carvacrol. Owing to their low toxicity and ability to cross the blood–brain barrier, EOs represent promising natural candidates for the development of complementary therapeutic strategies in PD. Further mechanistic and translational studies are warranted to substantiate their clinical potential.

氧化应激（OS）是由活性氧（ROS）和内源性抗氧化剂之间的失衡引起的，在包括帕金森病（PD）在内的神经退行性疾病的发病机制中起着核心作用。大脑的高需氧量和丰富的多不饱和脂肪酸使它特别容易受到ros引起的损伤。尽管研究取得了重大进展，但目前尚无PD的疾病改善治疗方法。因此，人们越来越关注具有抗氧化和神经保护特性的天然生物活性化合物。其中，精油（EOs），挥发性植物来源的混合物，具有抗氧化，抗炎和神经活性的作用，正在成为PD治疗的有前途的佐剂。本文在体外和体内神经退行性变模型中对特征明确的EOs的抗氧化和神经保护作用进行了严格的研究。截至2025年3月，在PubMed和Scopus中进行了文献检索，确定了在pd相关实验环境中调查EOs或其主要成分的研究。有证据表明，柑橘属和蔷薇属以及Lamiaceae家族的精油可以减少细胞内ROS积累，抑制脂质过氧化，增强内源性抗氧化酶活性，调节细胞凋亡和炎症途径。这些多靶点作用通常归因于EO成分之间的协同相互作用，如柠檬烯、芳樟醇、百里香酚和香芹酚。由于其低毒性和穿越血脑屏障的能力，EOs代表了PD补充治疗策略发展的有希望的天然候选者。进一步的机制和转化研究是必要的，以证实其临床潜力。

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引用次数: 0

Butein suppresses depolarization-evoked glutamate release by modulating P/Q-type Ca2+ channels and protein kinase C pathway in rat cortical synaptosomes 丁蛋白通过调节大鼠皮质突触体P/ q型Ca2+通道和蛋白激酶C途径抑制去极化诱发的谷氨酸释放。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2026-01-01 Epub Date: 2025-12-23 DOI: 10.1016/j.neuint.2025.106107

Ming-Shang Pai , Mao-Hsiang Hsiao , Ming-Yi Lee , Hsin Chang , Wei-Che Chiu , Su-Jane Wang

This study examined the effects of butein, a natural chalcone, on glutamate release from rat cortical synaptosomes and elucidated the underlying mechanisms. Using 4-aminopyridine (4-AP) to evoke glutamate releases, we found that butein inhibited evoked glutamate release in a concentration-dependent manner (IC₅₀ = 11.4 μM) without altering basal release. The inhibition required extracellular Ca²⁺, as it was prevented under Ca²⁺-free conditions. Butein attenuated 4-AP-induced cytosolic Ca²⁺ elevation without affecting membrane depolarization. Moreover, the inhibitory effect of butein on evoked glutamate release was prevented by blockade of vesicular glutamate transporters, P/Q-type Ca²⁺ channels or protein kinase C (PKC), but was unaffected by inhibition of N-type Ca²⁺ channels, protein kinase A (PKA), Ca²⁺/calmodulin-dependent kinase II (CaMKII), or mitogen-activated protein kinase (MAPK). Western blot analysis showed that butein suppressed 4-AP-induced phosphorylation of PKC, PKCα, and the downstream substrates myristoylated alanine-rich C-kinase substrate (MARCKS) and synaptosomal-associated protein-25 (SNAP-25). FM1-43 dye release and synaptotagmin 1 antibody (syt1-L ab) uptake assays further demonstrated that butein inhibits exocytotic vesicle release. Collectively, these findings indicate that butein inhibits evoked glutamate release from cortical nerve terminals by reducing P/Q-type Ca²⁺ channel–dependent Ca²⁺ influx and subsequently downregulating the PKC-mediated signaling pathways.

本研究考察了天然查尔酮——丁蛋白对大鼠皮层突触体谷氨酸释放的影响，并阐明了其潜在机制。利用4-氨基吡啶（4-AP）诱导谷氨酸释放，我们发现蛋白以浓度依赖的方式抑制诱发的谷氨酸释放（IC50 = 11.4 μM），而不改变基础释放。抑制需要细胞外Ca2+，因为它在Ca2+无条件下被阻止。丁蛋白减弱4- ap诱导的胞质Ca2+升高而不影响膜去极化。此外，通过阻断谷氨酸囊泡转运体、P/ q型Ca2+通道或蛋白激酶C (PKC)，可以阻止丁胺素对诱发谷氨酸释放的抑制作用，但对n型Ca2+通道、蛋白激酶A （PKA）、Ca2+/钙调素依赖性激酶II （CaMKII）或丝裂原活化蛋白激酶（MAPK）的抑制作用不受影响。Western blot分析显示，丁蛋白抑制4- ap诱导的PKC、PKCα、下游底物豆芽糖酰化富丙氨酸c激酶底物（MARCKS）和突触体相关蛋白-25 （SNAP-25）的磷酸化。FM1-43染料释放和synaptotagmin 1抗体（syt1-L ab）摄取实验进一步表明，丁蛋白抑制胞外囊泡释放。总的来说，这些发现表明，通过减少P/ q型Ca2+通道依赖的Ca2+内流并随后下调pkc介导的信号通路，蛋白抑制皮层神经末梢诱发的谷氨酸释放。

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引用次数: 0

A novel GSK3β inhibitor ameliorates tau aggregation and neuroinflammation in Alzheimer's disease 一种新的GSK3β抑制剂改善阿尔茨海默病的tau聚集和神经炎症。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2026-01-01 Epub Date: 2025-11-27 DOI: 10.1016/j.neuint.2025.106090

Xin-Yue Ning , Wen-Jie Liu , Li-Jun Zhou , Nan Wang , Xin-Zhu Li , Li-Meng Wu , Zhen-Shu Li , Ai-Zhu Yang , Si-Yuan Liu , Zong-He Xu , Fang-Hua Xun , Zi-Hua Xu , Qing-Chun Zhao

In Alzheimer's disease, increased GSK3β activity drives tau phosphorylation and directly or indirectly triggers neuroinflammation, neuronal damage and cognitive decline. We previously developed a novel GSK3β inhibitor, ZLWH-60, which demonstrated inhibitory activity with an IC50 of 11.5 nM. Here, we comprehensively evaluated the therapeutic potential of ZLWH-60 in suppressing tau pathology and neuroinflammation using multiple chemically-induced AD models. Our results demonstrate that ZLWH-60 could reduce the phosphorylation of multiple tau epitopes by inhibiting the activity of GSK3β, thereby ameliorating cognitive impairments in OKA-induced mouse model. In the LPS-induced mouse model, ZLWH-60 also reduced the secretion of inflammatory factors in the brain, exerting a neuroprotective effect. Our data highlight that ZLWH-60, as a GSK3β inhibitor, has a powerful ability to reduce the phosphorylation of tau protein and shift the balance of the inflammatory response from pro-inflammatory to anti-inflammatory, demonstrating the potential for therapeutic use of this drug to control AD.

在阿尔茨海默病中，GSK3β活性增加驱动tau磷酸化，直接或间接引发神经炎症、神经元损伤和认知能力下降。我们之前开发了一种新的GSK3β抑制剂ZLWH-60，显示出抑制活性，IC50为11.5 nM。在这里，我们通过多种化学诱导的AD模型，综合评估了ZLWH-60在抑制tau病理和神经炎症方面的治疗潜力。我们的研究结果表明，ZLWH-60可以通过抑制GSK3β的活性来降低多个tau表位的磷酸化，从而改善oka诱导的小鼠模型的认知障碍。在lps诱导小鼠模型中，ZLWH-60还能减少脑内炎症因子的分泌，发挥神经保护作用。我们的数据强调，ZLWH-60作为一种GSK3β抑制剂，具有降低tau蛋白磷酸化的强大能力，并将炎症反应的平衡从促炎转变为抗炎，这表明该药物具有控制AD的治疗潜力。

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引用次数: 0

BLF stimulates neuronal differentiation via activation of p35/CDK5 signaling and AMPK-mediated mitochondrial regulation BLF通过激活p35/CDK5信号和ampk介导的线粒体调控刺激神经元分化。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2026-01-01 Epub Date: 2025-12-23 DOI: 10.1016/j.neuint.2025.106106

Abdulkadir Cidem , Muhammet Oner , Gary Ro-Lin Chang , Chih-Ching Yen , Ke-Rong Chen , Shang-Hsun Yang , Ho Lin , Chuan-Mu Chen

Lactoferrin (LF) is a multifunctional glycoprotein with established roles in non-neuronal cell growth and differentiation and has underexplored potential in neurodevelopment. Here, we investigated bovine lactoferrin (bLF) as a neurotrophic agent, systematically evaluating its effects on neuronal differentiation, morphology, and mitochondrial regulation in PC12 cells. We demonstrated that bLF (50 μg/mL) induces neurite outgrowth comparable to nerve growth factor (NGF) while maintaining >90 % cell viability. Mechanistically, bLF activated TrkA by phosphorylation at Ser490, followed by ERK phosphorylation at Thr202/Tyr204 within 60 min, mirroring canonical NGF signaling. bLF also upregulates p35 (CDK5 activator) and phosphorylates Synapsin-I, driving presynaptic maturation. Structurally predicted to bind TrkA's ligand-binding interface, bLF synergizes with NGF to amplify differentiation outcomes. Furthermore, TMRE staining and AMPK phosphorylation assays revealed that bLF enhances axonal mitochondrial activity, surpassing NGF's effects. These results establish bLF as a multifunctional neurotrophic agent that coordinates TrkA-ERK-p35/CDK5 signaling, synaptic protein activation, and AMPK-driven mitochondrial regulation. Given its safety profile and synergy with endogenous neurotrophic pathways, bLF emerges as a promising candidate for neuroregenerative therapies targeting nerve injury or neurodegeneration.

乳铁蛋白（LF）是一种多功能糖蛋白，在非神经元细胞生长和分化中起着重要作用，但在神经发育中的潜力尚未得到充分发掘。在这里，我们研究了牛乳铁蛋白（bLF）作为一种神经营养剂，系统地评估了它对PC12细胞的神经元分化、形态和线粒体调节的影响。我们证明了bLF （50 μg/mL）诱导神经突生长，与神经生长因子（NGF）相当，同时保持bb0 - 90%的细胞活力。从机制上讲，bLF通过磷酸化Ser490激活TrkA，随后在60分钟内磷酸化ERK的Thr202/Tyr204，反映了典型的NGF信号传导。bLF也上调p35 （CDK5激活因子）和磷酸化synapsin - 1，推动突触前成熟。从结构上预测，bLF与TrkA的配体结合界面结合，与NGF协同作用以放大分化结果。此外，TMRE染色和AMPK磷酸化实验显示，bLF增强轴突线粒体活性，超过了NGF的作用。这些结果证实bLF是一种多功能神经营养剂，可协调TrkA-ERK-p35/CDK5信号，突触蛋白激活和ampk驱动的线粒体调节。鉴于其安全性和与内源性神经营养通路的协同作用，bLF成为针对神经损伤或神经变性的神经再生治疗的有希望的候选药物。

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引用次数: 0

Astaxanthin inhibits the aggregation and cytotoxicity of tau4RDΔK280 via possible interaction with the aggregation-prone segments 虾青素通过可能与易于聚集的片段相互作用抑制tau4RDΔK280的聚集和细胞毒性。

IF 4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international

Pub Date : 2026-01-01 Epub Date: 2025-12-11 DOI: 10.1016/j.neuint.2025.106103

Huahua Shi , Yan Zhao

Tauopathies are a group of neurodegenerative disorders characterized by the presence of abnormal aggregates of microtubule associated protein tau in the brain. In the most common tauopathy, Alzheimer's disease (AD), the aggregation of tau is closely linked with synaptic dysfunction and neuronal death, while targeting the aggregation of tau has been demonstrated to have therapeutic potential. Astaxanthin is a carotenoid with neuroprotective function, which has been shown to inhibit Aβ-induced pathology in AD animal and cell models. However, the effects of astaxanthin on tau aggregation and toxicity are much less explored. In this study, we generated a cell model of tauopathy overexpressing the amyloidogenic pro-aggregant tau repeat domains carrying the FTDP-17 mutation ΔK280 in N2a cells (N2a-tau_4RDΔK280). It was found that astaxanthin treatment alleviated the cytotoxicity of N2a-tau_4RDΔK280 cells while reducing the amount of tau_4RDΔK280 aggregates in the cells. Results from the thioflavin T aggregation assay demonstrated that astaxanthin inhibited the aggregation of tau_4RDΔK280 in vitro. Further analyses with transmission electron microscopy confirmed that astaxanthin reduced the formation of amyloid fibril structures of tau_4RDΔK280 in vitro. Thus, astaxanthin might inhibit the cytotoxicity of N2a-tau_4RDΔK280 cells by preventing the formation of tau_4RDΔK280 aggregates. Molecular docking simulation analyses revealed that astaxanthin was able to directly interact with tau_4RDΔK280 as well as several key aggregation-prone segments of tau protein. In conclusion, our results demonstrated that astaxanthin might exert neuroprotection by inhibiting the formation of tau aggregates via direct interaction with the key aggregation-prone segments.

tau病是一组神经退行性疾病，其特征是大脑中存在微管相关蛋白tau的异常聚集。在最常见的tau病阿尔茨海默病（AD）中，tau的聚集与突触功能障碍和神经元死亡密切相关，而靶向tau聚集已被证明具有治疗潜力。虾青素是一种具有神经保护功能的类胡萝卜素，在AD动物和细胞模型中已被证明可以抑制a β诱导的病理。然而，虾青素对tau聚集和毒性的影响却很少被探索。在这项研究中，我们在N2a细胞中建立了一个过表达携带FTDP-17突变ΔK280的淀粉样蛋白原聚集tau重复结构域的tau病细胞模型（N2a-tau4RDΔK280）。发现虾青素处理可以减轻N2a-tau4RDΔK280细胞的细胞毒性，同时减少细胞中tau4RDΔK280聚集体的数量。硫黄素T聚集实验结果表明虾青素在体外抑制tau4RDΔK280聚集。进一步的透射电镜分析证实虾青素在体外减少tau4RDΔK280淀粉样蛋白纤维结构的形成。因此，虾青素可能通过阻止tau4RDΔK280聚集体的形成来抑制N2a-tau4RDΔK280细胞的细胞毒性。分子对接模拟分析显示虾青素能够直接与tau4RDΔK280以及tau蛋白的几个关键聚集倾向片段相互作用。综上所述，我们的研究结果表明虾青素可能通过与关键聚集易感片段的直接相互作用，抑制tau聚集体的形成，从而发挥神经保护作用。

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引用次数: 0