Pub Date : 2025-10-21DOI: 10.1016/j.neulet.2025.138426
Cem Süer, Burak Tan, Nurcan Dursun, Bilal Koşar, Ercan Babur
This study examined the role of MAPKs in Tau phosphorylation and synaptic plasticity at perforant pathway–dentate gyrus (PP–DG) synapses following high-frequency stimulation (HFS). In vivo experiments were conducted on adult male Wistar rats under urethane anesthesia. Field potentials (fEPSP and PS) were recorded in the DG granule cell layer in response to PP stimulation. Western blotting assessed total and phosphorylated levels of Tau, ERK1/2, JNK, and P38 MAPK in HFS-induced hippocampus. MAPK inhibition disrupted early somatic potentiation when applied during induction, and JNK inhibition alone impaired late potentiation. Reduced somatic activity correlated with decreased MAPK phosphorylation and Tau phosphorylation at Ser422. Findings suggest that ERK1/2, JNK, and P38 are essential for Tau phosphorylation at Ser422 in HFS-induced hippocampal synapses.
{"title":"Site-Specific Regulation of Tau phosphorylation by MAPK pathways during HFS-Induced synaptic plasticity in the Rat hippocampus","authors":"Cem Süer, Burak Tan, Nurcan Dursun, Bilal Koşar, Ercan Babur","doi":"10.1016/j.neulet.2025.138426","DOIUrl":"10.1016/j.neulet.2025.138426","url":null,"abstract":"<div><div>This study examined the role of MAPKs in Tau phosphorylation and synaptic plasticity at perforant pathway–dentate gyrus (PP–DG) synapses following high-frequency stimulation (HFS). In vivo experiments were conducted on adult male Wistar rats under urethane anesthesia. Field potentials (fEPSP and PS) were recorded in the DG granule cell layer in response to PP stimulation. Western blotting assessed total and phosphorylated levels of Tau, ERK1/2, JNK, and P38 MAPK in HFS-induced hippocampus. MAPK inhibition disrupted early somatic potentiation when applied during induction, and JNK inhibition alone impaired late potentiation. Reduced somatic activity correlated with decreased MAPK phosphorylation and Tau phosphorylation at Ser422. Findings suggest that ERK1/2, JNK, and P38 are essential for Tau phosphorylation at Ser422 in HFS-induced hippocampal synapses.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"869 ","pages":"Article 138426"},"PeriodicalIF":2.0,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-20DOI: 10.1016/j.neulet.2025.138427
Shin-Young Park
Hippocalcin (HPCA), a neuronal Ca2+ sensor protein in the EF-hand superfamily, plays a key role in calcium signaling and neurological function in the central nervous system. This review highlights HPCA’s structure–function relationships and clinical significance. Through Ca2+-dependent conformational changes and a unique calcium-myristoyl switch, HPCA dynamically associates with membranes, acting as both sensor and effector. It modulates neuronal excitability, synaptic plasticity, neurodevelopment, and neuroprotection. Notably, HPCA is critical in mediating slow afterhyperpolarization, a key mechanism for adjusting neuronal firing patterns and maintaining excitability homeostasis. It also influences neural stem cell fate by promoting neuronal differentiation and suppressing astrocytic differentiation. HPCA maintains mitochondrial calcium homeostasis and activates survival pathways, protecting against apoptosis and oxidative stress. Its dysregulation is implicated in Alzheimer’s and Parkinson’s diseases, epilepsy, depression, schizophrenia, and dystonia. Given its restricted expression in the brain and multifaceted functional roles, further elucidation of HPCA-mediated signaling mechanisms is warranted to advance the development of targeted therapeutic strategies for a broad spectrum of neurological disorders.
{"title":"Mini-review: “Hippocalcin: Molecular mechanisms and therapeutic potential in neuronal function”","authors":"Shin-Young Park","doi":"10.1016/j.neulet.2025.138427","DOIUrl":"10.1016/j.neulet.2025.138427","url":null,"abstract":"<div><div>Hippocalcin (HPCA), a neuronal Ca<sup>2+</sup> sensor protein in the EF-hand superfamily, plays a key role in calcium signaling and neurological function in the central nervous system. This review highlights HPCA’s structure–function relationships and clinical significance. Through Ca2<sup>+</sup>-dependent conformational changes and a unique calcium-myristoyl switch, HPCA dynamically associates with membranes, acting as both sensor and effector. It modulates neuronal excitability, synaptic plasticity, neurodevelopment, and neuroprotection. Notably, HPCA is critical in mediating slow afterhyperpolarization, a key mechanism for adjusting neuronal firing patterns and maintaining excitability homeostasis. It also influences neural stem cell fate by promoting neuronal differentiation and suppressing astrocytic differentiation. HPCA maintains mitochondrial calcium homeostasis and activates survival pathways, protecting against apoptosis and oxidative stress. Its dysregulation is implicated in Alzheimer’s and Parkinson’s diseases, epilepsy, depression, schizophrenia, and dystonia. Given its restricted expression in the brain and multifaceted functional roles, further elucidation of HPCA-mediated signaling mechanisms is warranted to advance the development of targeted therapeutic strategies for a broad spectrum of neurological disorders.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"869 ","pages":"Article 138427"},"PeriodicalIF":2.0,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1016/j.neulet.2025.138424
Jee Hyun Yi
Impairments in working memory and cognitive flexibility are early and consistent features of both Alzheimer’s disease (AD) and stress. These functions depend critically on prefrontal cortical (PFC) circuits, which are particularly vulnerable to neuromodulatory and pathological insults. Recent studies suggest that stress and AD do not simply act globally, but instead converge on specific molecular and cellular targets within distinct neural populations. Notably, both chronic stress and Alzheimer’s disease models exhibit dysregulation of synaptic signaling via NR2B-containing NMDA receptors and aberrant GSK-3β activation. These changes often emerge in a cell-type-specific manner, affecting excitatory pyramidal neurons and vulnerable interneuron subtypes such as SST+, PV+, and VIP + cells. The resulting imbalance in excitation and inhibition disrupts the integrity of prefrontal circuits, impairing adaptive behavior. This review synthesizes evidence across molecular, cellular, and circuit levels to outline a framework in which stress and AD pathology converge on shared vulnerable pathways. Understanding how specific cell populations mediate this vulnerability may lead to targeted strategies for enhancing cognitive resilience in neurodegenerative and stress-related disorders.
{"title":"From stress to Alzheimer’s: A circuit-based framework for prefrontal cognitive dysfunction","authors":"Jee Hyun Yi","doi":"10.1016/j.neulet.2025.138424","DOIUrl":"10.1016/j.neulet.2025.138424","url":null,"abstract":"<div><div>Impairments in working memory and cognitive flexibility are early and consistent features of both Alzheimer’s disease (AD) and stress. These functions depend critically on prefrontal cortical (PFC) circuits, which are particularly vulnerable to neuromodulatory and pathological insults. Recent studies suggest that stress and AD do not simply act globally, but instead converge on specific molecular and cellular targets within distinct neural populations. Notably, both chronic stress and Alzheimer’s disease models exhibit dysregulation of synaptic signaling via NR2B-containing NMDA receptors and aberrant GSK-3β activation. These changes often emerge in a cell-type-specific manner, affecting excitatory pyramidal neurons and vulnerable interneuron subtypes such as SST+, PV+, and VIP + cells. The resulting imbalance in excitation and inhibition disrupts the integrity of prefrontal circuits, impairing adaptive behavior. This review synthesizes evidence across molecular, cellular, and circuit levels to outline a framework in which stress and AD pathology converge on shared vulnerable pathways. Understanding how specific cell populations mediate this vulnerability may lead to targeted strategies for enhancing cognitive resilience in neurodegenerative and stress-related disorders.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"869 ","pages":"Article 138424"},"PeriodicalIF":2.0,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145327029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-17DOI: 10.1016/j.neulet.2025.138425
Rubing Zhou, Dawei Song, Miao Li, Hua Gao
The role of neutrophils in spinal cord injury (SCI) remains incompletely understood due to the absence of effective intervention strategies. Some studies employing antibody-mediated neutrophil depletion (ND) in vivo have yielded various conclusions. However, the mechanism of ND remains unclear, and a comprehensive assessment of its effects was largely lacking prior to application. In this study, we aimed to evaluate neutrophil-related changes following ND in SCI. Hematological analysis revealed that ND attenuated the SCI-induced rise in neutrophil counts but had a negligible effect on baseline levels. The level of IL-1β and IL-8 increased in plasma and intact spinal cord after ND, but exhibited divergent changes post-SCI. Tissue concentrations of TNF-α were elevated in the intact spinal cord but declined following SCI with ND. Neutrophil elastase, a neutrophil cytoplasm-specific protein, increased in both intact and injured spinal cord following ND. Furthermore, ND did not markedly affect SCI-induced blood-spinal cord barrier (BSCB) leakage. These findings indicate that antibody-mediated ND produces complicated effects, rendering it a suboptimal approach for studying neutrophils’ contributions in SCI pathophysiology. Conclusions derived from this method should be interpreted with caution, and alternative strategies should be pursued to better elucidate the role of neutrophils in SCI.
{"title":"Limitations of antibody-mediated neutrophil depletion in understanding the role of neutrophils following spinal cord injury in mice","authors":"Rubing Zhou, Dawei Song, Miao Li, Hua Gao","doi":"10.1016/j.neulet.2025.138425","DOIUrl":"10.1016/j.neulet.2025.138425","url":null,"abstract":"<div><div>The role of neutrophils in spinal cord injury (SCI) remains incompletely understood due to the absence of effective intervention strategies. Some studies employing antibody-mediated neutrophil depletion (ND) in vivo have yielded various conclusions. However, the mechanism of ND remains unclear, and a comprehensive assessment of its effects was largely lacking prior to application. In this study, we aimed to evaluate neutrophil-related changes following ND in SCI. Hematological analysis revealed that ND attenuated the SCI-induced rise in neutrophil counts but had a negligible effect on baseline levels. The level of IL-1β and IL-8 increased in plasma and intact spinal cord after ND, but exhibited divergent changes post-SCI. Tissue concentrations of TNF-α were elevated in the intact spinal cord but declined following SCI with ND. Neutrophil elastase, a neutrophil cytoplasm-specific protein, increased in both intact and injured spinal cord following ND. Furthermore, ND did not markedly affect SCI-induced blood-spinal cord barrier (BSCB) leakage. These findings indicate that antibody-mediated ND produces complicated effects, rendering it a suboptimal approach for studying neutrophils’ contributions in SCI pathophysiology. Conclusions derived from this method should be interpreted with caution, and alternative strategies should be pursued to better elucidate the role of neutrophils in SCI.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"869 ","pages":"Article 138425"},"PeriodicalIF":2.0,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14Epub Date: 2025-08-05DOI: 10.1016/j.neulet.2025.138337
Yan Fang Mao, Liang Chen, Jun Yu Liu, Zhang Yu Guo, Pei Lin Lu, Yan Xing Chen
Brain insulin signaling deficits contribute to multiple pathologicalfeatures of Alzheimer's disease (AD).Intranasal insulin has demonstrated therapeutic potential, but its underlying mechanisms remain unclear. This study investigated whether intranasal insulinmodulates tau pathology in early-stage APPswe/PS1dE9 (APP/PS1) mice.After six weeks of treatment, no significant changes in total or phosphorylated tau levels were observed. However, there was a trend toward improvement in dysregulated signaling pathways associated with tau kinases. These findings suggest that the protective effect of nasal insulin in early AD may not primarily be against tau-related neurotoxicity.
{"title":"Intranasal insulin administration shows limited tau-targeted effects in early-stage APP/PS1 Alzheimer's mice.","authors":"Yan Fang Mao, Liang Chen, Jun Yu Liu, Zhang Yu Guo, Pei Lin Lu, Yan Xing Chen","doi":"10.1016/j.neulet.2025.138337","DOIUrl":"10.1016/j.neulet.2025.138337","url":null,"abstract":"<p><p>Brain insulin signaling deficits contribute to multiple pathologicalfeatures of Alzheimer's disease (AD).Intranasal insulin has demonstrated therapeutic potential, but its underlying mechanisms remain unclear. This study investigated whether intranasal insulinmodulates tau pathology in early-stage APPswe/PS1dE9 (APP/PS1) mice.After six weeks of treatment, no significant changes in total or phosphorylated tau levels were observed. However, there was a trend toward improvement in dysregulated signaling pathways associated with tau kinases. These findings suggest that the protective effect of nasal insulin in early AD may not primarily be against tau-related neurotoxicity.</p>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":" ","pages":"138337"},"PeriodicalIF":2.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14Epub Date: 2025-07-27DOI: 10.1016/j.neulet.2025.138332
Liquan Qiu, Licai Zhang, Bin Fan, Xue Luo
Background: Sevoflurane anesthesia, while widely used, is associated with several side effects including the potential for nerve damage. MicroRNAs are disrupted in patients with sevoflurane anesthesia, including miR-423-3p. However, the association between miR-423-3p and neurological damage remains to be elucidated.
Aim: To investigate the effect of miR-423-3p on the rats after sevoflurane anesthesia and related molecular mechanisms.
Methods: RT-qPCR was utilized to quantify the levels of miR-423-3p, GPX4 and oxidative stress indicators in rat hippocampus. Cognitive function was assessed through the Morris water maze and novel object recognition tests. ELISA was applied to detect the levels of inflammatory factors.
Results: In the Sev group, miR-423-3p expression was significantly elevated, while GPX4 expression was markedly reduced. Down-regulated miR-423-3p negatively regulated GPX4 to shorten escape latency while increasing crossing times of the platform, time spend in the target quadrant, relative occupancy of exploring new objects and time to explore new objects. Furthermore, down-regulated miR-423-3p reduced ROS and MDA levels and increased GSH levels in nerve-injured rats, which could be reversed by inhibited GPX4. miR-423-3p inhibition reduced the levels of NLRP3, Caspase-1, IL-8, and IL-1β, which could be rescued by inhibition of GPX4.
Conclusion: Down-regulation of miR-423-3p attenuated cognitive deficits in nerve-injured rats. Moreover, repressed miR-423-3p mitigated oxidative stress and inflammation by negatively regulating GPX4.
{"title":"miR-423-3p alleviates sevoflurane-induced learning and memory dysfunction and nerve damage via negative regulation of GPX4.","authors":"Liquan Qiu, Licai Zhang, Bin Fan, Xue Luo","doi":"10.1016/j.neulet.2025.138332","DOIUrl":"10.1016/j.neulet.2025.138332","url":null,"abstract":"<p><strong>Background: </strong>Sevoflurane anesthesia, while widely used, is associated with several side effects including the potential for nerve damage. MicroRNAs are disrupted in patients with sevoflurane anesthesia, including miR-423-3p. However, the association between miR-423-3p and neurological damage remains to be elucidated.</p><p><strong>Aim: </strong>To investigate the effect of miR-423-3p on the rats after sevoflurane anesthesia and related molecular mechanisms.</p><p><strong>Methods: </strong>RT-qPCR was utilized to quantify the levels of miR-423-3p, GPX4 and oxidative stress indicators in rat hippocampus. Cognitive function was assessed through the Morris water maze and novel object recognition tests. ELISA was applied to detect the levels of inflammatory factors.</p><p><strong>Results: </strong>In the Sev group, miR-423-3p expression was significantly elevated, while GPX4 expression was markedly reduced. Down-regulated miR-423-3p negatively regulated GPX4 to shorten escape latency while increasing crossing times of the platform, time spend in the target quadrant, relative occupancy of exploring new objects and time to explore new objects. Furthermore, down-regulated miR-423-3p reduced ROS and MDA levels and increased GSH levels in nerve-injured rats, which could be reversed by inhibited GPX4. miR-423-3p inhibition reduced the levels of NLRP3, Caspase-1, IL-8, and IL-1β, which could be rescued by inhibition of GPX4.</p><p><strong>Conclusion: </strong>Down-regulation of miR-423-3p attenuated cognitive deficits in nerve-injured rats. Moreover, repressed miR-423-3p mitigated oxidative stress and inflammation by negatively regulating GPX4.</p>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":" ","pages":"138332"},"PeriodicalIF":2.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144743337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14Epub Date: 2025-08-06DOI: 10.1016/j.neulet.2025.138339
Yan Li, Qian Gao, Chenyu Zhuang, Yifan Zhou, Zixin Chang, Yingying Zhao, Shenfan Zhu, Yanqing Liu, Bo Zhang
Background: Alzheimer's disease (AD) is a neurodegenerative disorder that accounts for almost half of all dementia cases globally and is progressively increasing. Etiology includes heredity, genetic factors, aging, and nutrition, but sex hormones also play a key role. Reliable animal models of AD are the basis for gaining insight into the pathophysiological mechanisms of AD and for developing and evaluating novel therapeutic strategies for preclinical AD.
New method: This study described and evaluated a model mimicking features of late-onset AD by combining gonadectomy with bilateral hippocampal dentate gyrus Aβ injections in mice.
Results: As demonstrated by the Morris water maze test, Nissl staining, TUNEL, and EDU labeling, this method produced the mouse model of AD with decreased learning memory capacity accompanied by decreased neuronal function in the hippocampus, increased apoptotic neurons in hippocampus CA1 area and decreased regenerative neurons in hippocampus dentate gyrus area.
Comparison with existing methods: Existing AD models often overlook the physiological feature of sex hormone deficiency in late-onset AD and fail to fully account for the neuroprotective effects of sex hormones, which may lead to false-positive results in neuroprotection-related assessments. The model in this study simulates low sex hormone levels through gonadectomy and is combined with bilateral hippocampal dentate gyrus injection of Aβ1-42 oligomers, overcoming the limitations of single-factor models and more effectively simulating the pathophysiological characteristics of sex hormone deficiency and Aβ deposition in late-onset AD.
Conclusions: The model effectively simulated the pathophysiological state of late-onset AD. In both sexes, most of these indications of dysfunction were significantly more pronounced in gonadectomized animals compared to gonadally intact controls.
Significance statement: In this study, a mouse model of late-onset Alzheimer's disease, developed by combining gonadectomy with Aβ injection into the bilateral hippocampal dentate gyrus, accurately simulates the pathophysiological processes of sex hormone deficiency and Aβ deposition in patients, thereby providing a robust platform to explore nervous system structural and functional changes in late-onset AD and evaluate potential preventive drugs. Moreover, this dual-factor model provides novel insights into the synergistic interaction between sex hormone deficiency and Aβ pathology, offering a physiologically relevant platform for studying late-onset AD.
{"title":"Modeling Alzheimer's disease in mice: Gonadectomy combined with bilateral hippocampus dentate gyrus injection of Aβ<sub>1-42</sub> oligomers.","authors":"Yan Li, Qian Gao, Chenyu Zhuang, Yifan Zhou, Zixin Chang, Yingying Zhao, Shenfan Zhu, Yanqing Liu, Bo Zhang","doi":"10.1016/j.neulet.2025.138339","DOIUrl":"10.1016/j.neulet.2025.138339","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is a neurodegenerative disorder that accounts for almost half of all dementia cases globally and is progressively increasing. Etiology includes heredity, genetic factors, aging, and nutrition, but sex hormones also play a key role. Reliable animal models of AD are the basis for gaining insight into the pathophysiological mechanisms of AD and for developing and evaluating novel therapeutic strategies for preclinical AD.</p><p><strong>New method: </strong>This study described and evaluated a model mimicking features of late-onset AD by combining gonadectomy with bilateral hippocampal dentate gyrus Aβ injections in mice.</p><p><strong>Results: </strong>As demonstrated by the Morris water maze test, Nissl staining, TUNEL, and EDU labeling, this method produced the mouse model of AD with decreased learning memory capacity accompanied by decreased neuronal function in the hippocampus, increased apoptotic neurons in hippocampus CA1 area and decreased regenerative neurons in hippocampus dentate gyrus area.</p><p><strong>Comparison with existing methods: </strong>Existing AD models often overlook the physiological feature of sex hormone deficiency in late-onset AD and fail to fully account for the neuroprotective effects of sex hormones, which may lead to false-positive results in neuroprotection-related assessments. The model in this study simulates low sex hormone levels through gonadectomy and is combined with bilateral hippocampal dentate gyrus injection of Aβ<sub>1-42</sub> oligomers, overcoming the limitations of single-factor models and more effectively simulating the pathophysiological characteristics of sex hormone deficiency and Aβ deposition in late-onset AD.</p><p><strong>Conclusions: </strong>The model effectively simulated the pathophysiological state of late-onset AD. In both sexes, most of these indications of dysfunction were significantly more pronounced in gonadectomized animals compared to gonadally intact controls.</p><p><strong>Significance statement: </strong>In this study, a mouse model of late-onset Alzheimer's disease, developed by combining gonadectomy with Aβ injection into the bilateral hippocampal dentate gyrus, accurately simulates the pathophysiological processes of sex hormone deficiency and Aβ deposition in patients, thereby providing a robust platform to explore nervous system structural and functional changes in late-onset AD and evaluate potential preventive drugs. Moreover, this dual-factor model provides novel insights into the synergistic interaction between sex hormone deficiency and Aβ pathology, offering a physiologically relevant platform for studying late-onset AD.</p>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":" ","pages":"138339"},"PeriodicalIF":2.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14Epub Date: 2025-08-08DOI: 10.1016/j.neulet.2025.138347
Hsien-Hui Chung
Maternal diabetes (MD) increases the risk for neurodevelopmental disorders and leads to neural tube defects (NTDs) which are severe anomalies of the nervous system. In order to elucidate the etiology and pathological mechanisms causing NTDs in MD and try to search for new therapeutic strategies as well, the exposure of induced pluripotency stem cell (iPSC)-neural stem cells (NSCs) to high glucose (HG) may be associated with fetal progressive deterioration of neuronal functions in utero ultimately leading to MD-related NTDs. In the present study, although HG (25 mM) had no effect on the viability of undifferentiated iPSC-NSCs compared with the positive control mannitol (25 mM), HG attenuated iPSC-NSCs cell proliferation and induced the presence of decreased βIII-tubulin and neurite network length during 7-day neuronal differentiation, resulting in the inability of nerve-to-nerve connections to communicate effectively. Compared with mannitol, HG actually reduced gene and protein expressions of iPSC-NSCs differentiation marker βIII-tubulin on day 7. Moreover, HG increased protein expressions of caspase-1 during 7-day neuronal differentiation compared with mannitol, indicating the critical role of caspase-1 in HG-mediated neuronal inflammation. Thus, the present study indicated that HG-induced impairment in iPSC-NSCs differentiation was mediated by decreased βIII-tubulin, shorter neurite network length and increased caspase-1 expressions, which provided a direction for the clarification of MD-induced NTDs.
产妇糖尿病（MD）增加了神经发育障碍的风险，并导致神经管缺陷（NTDs），这是神经系统的严重异常。为了阐明MD中NTDs的病因和病理机制，并试图寻找新的治疗策略，诱导多能干细胞(iPSC)-神经干细胞（NSCs）暴露于高糖（HG）可能与胎儿在子宫内神经元功能的进行性恶化有关，最终导致MD相关的NTDs。在本研究中，虽然HG（25 mM）与阳性对照甘露醇（25 mM）相比，对未分化iPSC-NSCs的活力没有影响，但在7天的神经元分化过程中，HG减弱了iPSC-NSCs细胞的增殖，诱导β iii -微管蛋白和神经突网络长度的减少，导致神经间连接无法有效沟通。与甘露醇相比，HG在第7天实际上降低了iPSC-NSCs分化标志物β iii -微管蛋白的基因和蛋白表达。此外，与甘露醇相比，HG在7天的神经元分化过程中增加了caspase-1的蛋白表达，这表明caspase-1在HG介导的神经元炎症中起着关键作用。因此，本研究表明，hg诱导的iPSC-NSCs分化障碍是通过β iii -微管蛋白减少、神经突网络长度缩短和caspase-1表达增加介导的，这为阐明md诱导的NTDs提供了方向。
{"title":"The dysregulation of high glucose-induced iPSC-neural stem cells differentiation by caspase-1.","authors":"Hsien-Hui Chung","doi":"10.1016/j.neulet.2025.138347","DOIUrl":"10.1016/j.neulet.2025.138347","url":null,"abstract":"<p><p>Maternal diabetes (MD) increases the risk for neurodevelopmental disorders and leads to neural tube defects (NTDs) which are severe anomalies of the nervous system. In order to elucidate the etiology and pathological mechanisms causing NTDs in MD and try to search for new therapeutic strategies as well, the exposure of induced pluripotency stem cell (iPSC)-neural stem cells (NSCs) to high glucose (HG) may be associated with fetal progressive deterioration of neuronal functions in utero ultimately leading to MD-related NTDs. In the present study, although HG (25 mM) had no effect on the viability of undifferentiated iPSC-NSCs compared with the positive control mannitol (25 mM), HG attenuated iPSC-NSCs cell proliferation and induced the presence of decreased βIII-tubulin and neurite network length during 7-day neuronal differentiation, resulting in the inability of nerve-to-nerve connections to communicate effectively. Compared with mannitol, HG actually reduced gene and protein expressions of iPSC-NSCs differentiation marker βIII-tubulin on day 7. Moreover, HG increased protein expressions of caspase-1 during 7-day neuronal differentiation compared with mannitol, indicating the critical role of caspase-1 in HG-mediated neuronal inflammation. Thus, the present study indicated that HG-induced impairment in iPSC-NSCs differentiation was mediated by decreased βIII-tubulin, shorter neurite network length and increased caspase-1 expressions, which provided a direction for the clarification of MD-induced NTDs.</p>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":" ","pages":"138347"},"PeriodicalIF":2.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The current study aims to evaluate any potential anxiolytic effects and the action mechanisms of ferulic acid, a phenolic phytochemical compound, in mice. The anxiolytic activity of ferulic acid at the doses of 0.1, 1, 10, and 100 mg/kg, p.o in female BALB/c mice was assessed by open field, hole-board and elevated plus maze tests. The possible roles of noradrenergic, serotonergic, and GABAergic modulation in the anxiolytic action of 100 mg/kg ferulic acid were also investigated by pretreatment with 5 mg/kg (i.p.) yohimbine, 1 mg/kg (i.p.) WAY-100635, and 3 mg/kg (i.p.) flumazenil, respectively, in the hole-board and open field tests. Similar to the positive standard diazepam (1 mg/kg, i.p); without altering the locomotor activity, 100 mg/kg ferulic acid significantly altered all the parameters related to anxiolytic activity, whereas 0.1 and 10 mg/kg doses were found to be effective in only some parameters in elevated plus-maze and open field tests, suggesting a U-shaped dose–response pattern. The anxiolytic effect of 100 mg/kg ferulic acid was significantly antagonized by the pretreatment with 5-HT1A receptor antagonist WAY-100635 and especially by α-2 adrenoceptor antagonist yohimbine while the anxiolytic action was not blocked by GABAA/BZ receptor antagonist flumazenil pretreatment. The findings imply that ferulic acid’s anxiolytic effect is mediated by the activation of α-2 adrenoceptors and 5-HT1A receptors. In conclusion, it is possible to say that ferulic acid can be a safe potential agent which that be used alone or in combination with current effective treatments for anxiety.
{"title":"Ferulic acid possesses anxiolytic activity: evidence for the involvement of serotonergic and noradrenergic systems","authors":"Ozlem Pınar Cetiner , Hazal Eken , Feyza Alyu Altınok , Rana Arslan , Nurcan Bektas","doi":"10.1016/j.neulet.2025.138416","DOIUrl":"10.1016/j.neulet.2025.138416","url":null,"abstract":"<div><div>The current study aims to evaluate any potential anxiolytic effects and the action mechanisms of ferulic acid, a phenolic phytochemical compound, in mice. The anxiolytic activity of ferulic acid at the doses of 0.1, 1, 10, and 100 mg/kg, <em>p.o</em> in female BALB/c mice was assessed by open field, hole-board and elevated plus maze tests. The possible roles of noradrenergic, serotonergic, and GABAergic modulation in the anxiolytic action of 100 mg/kg ferulic acid were also investigated by pretreatment with 5 mg/kg (<em>i.p.</em>) yohimbine, 1 mg/kg (<em>i.p.</em>) WAY-100635, and 3 mg/kg (<em>i.p.</em>) flumazenil, respectively, in the hole-board and open field tests. Similar to the positive standard diazepam (1 mg/kg, i.p); without altering the locomotor activity, 100 mg/kg ferulic acid significantly altered all the parameters related to anxiolytic activity, whereas 0.1 and 10 mg/kg doses were found to be effective in only some parameters in elevated plus-maze and open field tests, suggesting a U-shaped dose–response pattern. The anxiolytic effect of 100 mg/kg ferulic acid was significantly antagonized by the pretreatment with 5-HT<sub>1A</sub> receptor antagonist WAY-100635 and especially by α-2 adrenoceptor antagonist yohimbine while the anxiolytic action was not blocked by GABA<sub>A</sub>/BZ receptor antagonist flumazenil pretreatment. The findings imply that ferulic acid’s anxiolytic effect is mediated by the activation of α-2 adrenoceptors and 5-HT<sub>1A</sub> receptors. In conclusion, it is possible to say that ferulic acid can be a safe potential agent which that be used alone or in combination with current effective treatments for anxiety.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"869 ","pages":"Article 138416"},"PeriodicalIF":2.0,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145293055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Parkinson’s disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra, where oxidative stress and apoptosis play central roles. Epidemiological evidence suggests that nicotine may exert neuroprotective effects, but the molecular mechanisms remain incompletely understood. This study investigated whether nicotine mitigates MPTP-induced neurotoxicity in mice through modulation of the BDNF/PI3K/AKT/Nrf2 signaling pathway.
Male BALB/c mice were divided into control, nicotine, MPTP, and MPTP + nicotine groups. Histological analysis revealed that nicotine significantly reduced MPTP-induced neuronal pyknosis and preserved tyrosine hydroxylase-positive dopaminergic neurons. Biochemical assays showed that nicotine attenuated MPTP-induced increases in malondialdehyde, lactate dehydrogenase, and lactate/pyruvate ratio, while restoring complex I activity and antioxidant enzyme activities (SOD, CAT, GPx, GR). Western blotting demonstrated that nicotine reversed MPTP-induced suppression of phosphorylated PI3K, AKT, and Nrf2, and shifted apoptotic signaling toward survival by increasing Bcl-2 and reducing Bax and Bad.
Importantly, nicotine restored BDNF levels in the substantia nigra, and ex vivo experiments confirmed that nicotine upregulated BDNF via α7 nicotinic acetylcholine receptor activation. These findings suggest that nicotine confers neuroprotection by enhancing BDNF-mediated activation of the PI3K/AKT/Nrf2 axis, leading to improved antioxidant defenses and anti-apoptotic signaling.
In conclusion, nicotine mitigates MPTP-induced dopaminergic neurodegeneration via BDNF/PI3K/AKT/Nrf2 signaling. While nicotine’s addictive properties limit its therapeutic use, selective targeting of nicotinic pathways may represent a promising strategy for disease-modifying interventions in PD.
{"title":"The role of BDNF/PI3K/AKT/Nrf2 signaling in nicotine’s protective effects against MPTP-induced Parkinson’s disease","authors":"Nikoloz Zhgenti , Ekaterine Bakuradze , Otar Bibilashvili , Nana Koshoridze","doi":"10.1016/j.neulet.2025.138412","DOIUrl":"10.1016/j.neulet.2025.138412","url":null,"abstract":"<div><div>Parkinson’s disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra, where oxidative stress and apoptosis play central roles. Epidemiological evidence suggests that nicotine may exert neuroprotective effects, but the molecular mechanisms remain incompletely understood. This study investigated whether nicotine mitigates MPTP-induced neurotoxicity in mice through modulation of the BDNF/PI3K/AKT/Nrf2 signaling pathway.</div><div>Male BALB/c mice were divided into control, nicotine, MPTP, and MPTP + nicotine groups. Histological analysis revealed that nicotine significantly reduced MPTP-induced neuronal pyknosis and preserved tyrosine hydroxylase-positive dopaminergic neurons. Biochemical assays showed that nicotine attenuated MPTP-induced increases in malondialdehyde, lactate dehydrogenase, and lactate/pyruvate ratio, while restoring complex I activity and antioxidant enzyme activities (SOD, CAT, GPx, GR). Western blotting demonstrated that nicotine reversed MPTP-induced suppression of phosphorylated PI3K, AKT, and Nrf2, and shifted apoptotic signaling toward survival by increasing Bcl-2 and reducing Bax and Bad.</div><div>Importantly, nicotine restored BDNF levels in the substantia nigra, and ex vivo experiments confirmed that nicotine upregulated BDNF via α7 nicotinic acetylcholine receptor activation. These findings suggest that nicotine confers neuroprotection by enhancing BDNF-mediated activation of the PI3K/AKT/Nrf2 axis, leading to improved antioxidant defenses and anti-apoptotic signaling.</div><div>In conclusion, nicotine mitigates MPTP-induced dopaminergic neurodegeneration via BDNF/PI3K/AKT/Nrf2 signaling. While nicotine’s addictive properties limit its therapeutic use, selective targeting of nicotinic pathways may represent a promising strategy for disease-modifying interventions in PD.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"868 ","pages":"Article 138412"},"PeriodicalIF":2.0,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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