Neurochemistry international最新文献

{"title":"USP53 promotes NOTCH2-induced neuroinflammation in Alzheimer's disease","authors":"Dandan He ,&nbsp;Huajian Zhao ,&nbsp;Yong Zhu ,&nbsp;Yufei Kou ,&nbsp;Tao Liu ,&nbsp;Huahai Huang ,&nbsp;Haiming Yang ,&nbsp;Lihua Zhang ,&nbsp;Jingyue Deng ,&nbsp;Feng Xu ,&nbsp;Qingyong Wang","doi":"10.1016/j.neuint.2025.106109","DOIUrl":"10.1016/j.neuint.2025.106109","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aimed to investigate the role of USP53 and its associated signaling pathway associated with USP53 in Alzheimer's disease (AD).</div></div><div><h3>Methods</h3><div><em>In vivo</em> experiments were conducted in C57BL/6, 5XFAD, and USP53-knockout 5XFAD (USP53^−/−) mice. <em>In vitro</em> experiments were performed using primary human microglia cells. mRNA expression was examined using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Protein expression was measured using western blotting and immunofluorescence (IF). Immunoprecipitation (Co-IP) was used to detect protein-protein interactions. Morris Water Maze (MWM) was used to evaluate the learning ability and memory of mice.</div></div><div><h3>Results</h3><div>USP53 was overexpressed in patients with AD. Knockout of USP53 downregulated the expression of CD68, glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba1) and neuronal nuclear protein (NeuN), as well as the inflammatory mediators, interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α). The accumulation of Tau protein was reduced, and the learning ability and memory was improved in USP53^−/− mice compared to 5XFAD mice. <em>In vitro</em> experiments demonstrated that protein-protein interaction existed between USP53 and NOTCH2 and that the inhibition of USP53 prevented amyloid-beta (Aβ)-induced deubiquitination of NOTCH2. Knockdown of USP53 reduced Aβ-induced elevation of inflammatory mediators and repressed Aβ-induced activation of IKKβ/NFκB signaling pathway in microglia.</div></div><div><h3>Conclusion</h3><div>USP53 promotes the activation of neuroinflammation and worsens learning ability and memory in AD mice, mediated by NOTCH2.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"193 ","pages":"Article 106109"},"PeriodicalIF":4.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145891964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the role of GABAergic interneurons in the antidepressant-like mechanism of agomelatine","authors":"Suhong Ye ,&nbsp;Qiaolu Xu ,&nbsp;Nashwa Amin ,&nbsp;Ling Bao ,&nbsp;Yang Yang ,&nbsp;Irum Naz Abbasi ,&nbsp;Marong Fang","doi":"10.1016/j.neuint.2025.106101","DOIUrl":"10.1016/j.neuint.2025.106101","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106101"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145734559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the critical role of ceramide in the pathogenesis of Alzheimer's disease and its clinical significance","authors":"Yi-Wen Huang ,&nbsp;Hua-Chen Chan ,&nbsp;Jing-Yi Khoo ,&nbsp;Mei-Lin Chan ,&nbsp;Daniel Bender ,&nbsp;Vinoth Kumar Ponnusamy ,&nbsp;Abdel Ali Belaidi ,&nbsp;Liang-Yin Ke","doi":"10.1016/j.neuint.2025.106104","DOIUrl":"10.1016/j.neuint.2025.106104","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, and synaptic loss. Emerging evidence indicates that <em>apolipoprotein E</em> (<em>APOE</em>) 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.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106104"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145766786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPR55 deficiency exacerbates cognitive impairments and Alzheimer's disease-like pathology in mice","authors":"Bing Fan ,&nbsp;YuSheng Liang ,&nbsp;TianTian Zhi ,&nbsp;Lei Wu ,&nbsp;YangXia Wu ,&nbsp;Yan Yang ,&nbsp;Zhi Xie ,&nbsp;Xian Wu","doi":"10.1016/j.neuint.2025.106105","DOIUrl":"10.1016/j.neuint.2025.106105","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusions</h3><div>These findings underscore the critical role of GPR55 in AD progression and highlight its potential as a therapeutic target for AD treatment.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106105"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SPI1 suppresses YAP phosphorylation in vascular endothelial cells to prevent intracranial aneurysm progression","authors":"Yikui Liu ,&nbsp;Danyi Zheng ,&nbsp;Lanlan Zhao ,&nbsp;Bing Leng ,&nbsp;Qingfang Sun ,&nbsp;Liuguan Bian ,&nbsp;Yongtao Zheng","doi":"10.1016/j.neuint.2025.106100","DOIUrl":"10.1016/j.neuint.2025.106100","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106100"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145734557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ERBB4 colocalizes with phosphorylated tau aggregates in multiple tauopathies","authors":"Chihiro Matsumoto ,&nbsp;Tomohiro Kabuta ,&nbsp;Terunori Sano ,&nbsp;Shigeo Murayama ,&nbsp;Yuko Saito ,&nbsp;Yuji Takahashi","doi":"10.1016/j.neuint.2025.106093","DOIUrl":"10.1016/j.neuint.2025.106093","url":null,"abstract":"<div><div>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 <em>MAPT</em> 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.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106093"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Essential oils by name and by nature: a review of their antioxidant and neuroprotective potential in Parkinson's disease","authors":"Claudia Cannas ,&nbsp;Stefano Zoroddu ,&nbsp;Alessandra Tiziana Peana ,&nbsp;Gaia Rocchitta ,&nbsp;Luigi Bagella ,&nbsp;Rossana Migheli","doi":"10.1016/j.neuint.2025.106092","DOIUrl":"10.1016/j.neuint.2025.106092","url":null,"abstract":"<div><div>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 <em>in vitro</em> and <em>in vivo</em> 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 <em>Citrus</em> and <em>Rosa</em> genus, and the <em>Lamiaceae</em> 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.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106092"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Butein suppresses depolarization-evoked glutamate release by modulating P/Q-type Ca2+ channels and protein kinase C pathway in rat cortical synaptosomes","authors":"Ming-Shang Pai ,&nbsp;Mao-Hsiang Hsiao ,&nbsp;Ming-Yi Lee ,&nbsp;Hsin Chang ,&nbsp;Wei-Che Chiu ,&nbsp;Su-Jane Wang","doi":"10.1016/j.neuint.2025.106107","DOIUrl":"10.1016/j.neuint.2025.106107","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106107"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145831847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel GSK3β inhibitor ameliorates tau aggregation and neuroinflammation in Alzheimer's disease","authors":"Xin-Yue Ning ,&nbsp;Wen-Jie Liu ,&nbsp;Li-Jun Zhou ,&nbsp;Nan Wang ,&nbsp;Xin-Zhu Li ,&nbsp;Li-Meng Wu ,&nbsp;Zhen-Shu Li ,&nbsp;Ai-Zhu Yang ,&nbsp;Si-Yuan Liu ,&nbsp;Zong-He Xu ,&nbsp;Fang-Hua Xun ,&nbsp;Zi-Hua Xu ,&nbsp;Qing-Chun Zhao","doi":"10.1016/j.neuint.2025.106090","DOIUrl":"10.1016/j.neuint.2025.106090","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106090"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BLF stimulates neuronal differentiation via activation of p35/CDK5 signaling and AMPK-mediated mitochondrial regulation","authors":"Abdulkadir Cidem ,&nbsp;Muhammet Oner ,&nbsp;Gary Ro-Lin Chang ,&nbsp;Chih-Ching Yen ,&nbsp;Ke-Rong Chen ,&nbsp;Shang-Hsun Yang ,&nbsp;Ho Lin ,&nbsp;Chuan-Mu Chen","doi":"10.1016/j.neuint.2025.106106","DOIUrl":"10.1016/j.neuint.2025.106106","url":null,"abstract":"<div><div>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 &gt;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.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106106"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145831884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}