Pub Date : 2025-10-09DOI: 10.1016/j.neuint.2025.106071
Ly Huong Nguyen , Loc Dinh Nguyen , Dat Xuan Dao , Tsuyoshi Hattori , Hiroshi Ishii , Mika Takarada-Iemata , Osamu Hori
The unfolded protein response (UPR) is activated under different neuropathological conditions, such as brain ischemia, epilepsy, and neurodegeneration. We previously reported that a UPR transducer, activating transcription factor 6 (ATF6), and its downstream molecular chaperones in the endoplasmic reticulum (ER) have neuroprotective properties against excitotoxicity. In this study, we examined the temporal and spatial changes in the UPR activation after administration of an excitotoxic reagent, kainate (KA), into mice. RT-qPCR revealed enhanced expression of UPR genes, with peaks either on day 1 or day 3 after intrahippocampal KA injection. The status of the UPR was analyzed using ER stress-activated indicator (ERAI)-transgenic mice, in which the spliced form of XBP-1, downstream of the IRE1 branch of the UPR, can be monitored. ERAI-derived GFP signals were strongly observed in CA3 neurons and moderately observed in dentate gyrus neurons, but not in CA1 neurons, after KA injection. A small portion of the activated astrocytes was also positive for ERAI signals. Further studies revealed that ERAI signals were observed in both the soma and dendrites of neurons in regions with enhanced neuronal activity and resistance to KA toxicity. These results suggest that the UPR may be associated with the neuronal activity and survival after KA injection.
{"title":"Regional and cell type-specific activation of the unfolded protein response after kainate injection in mice","authors":"Ly Huong Nguyen , Loc Dinh Nguyen , Dat Xuan Dao , Tsuyoshi Hattori , Hiroshi Ishii , Mika Takarada-Iemata , Osamu Hori","doi":"10.1016/j.neuint.2025.106071","DOIUrl":"10.1016/j.neuint.2025.106071","url":null,"abstract":"<div><div>The unfolded protein response (UPR) is activated under different neuropathological conditions, such as brain ischemia, epilepsy, and neurodegeneration. We previously reported that a UPR transducer, activating transcription factor 6 (ATF6), and its downstream molecular chaperones in the endoplasmic reticulum (ER) have neuroprotective properties against excitotoxicity. In this study, we examined the temporal and spatial changes in the UPR activation after administration of an excitotoxic reagent, kainate (KA), into mice. RT-qPCR revealed enhanced expression of UPR genes, with peaks either on day 1 or day 3 after intrahippocampal KA injection. The status of the UPR was analyzed using ER stress-activated indicator (ERAI)-transgenic mice, in which the spliced form of XBP-1, downstream of the IRE1 branch of the UPR, can be monitored. ERAI-derived GFP signals were strongly observed in CA3 neurons and moderately observed in dentate gyrus neurons, but not in CA1 neurons, after KA injection. A small portion of the activated astrocytes was also positive for ERAI signals. Further studies revealed that ERAI signals were observed in both the soma and dendrites of neurons in regions with enhanced neuronal activity and resistance to KA toxicity. These results suggest that the UPR may be associated with the neuronal activity and survival after KA injection.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106071"},"PeriodicalIF":4.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257016","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}
The blood-brain barrier is an anatomical structure responsible for controlling the flux of nutrients, metabolites, and xenobiotics into and out of the brain. This fundamental function is carried out through the coordinated action of specific ion channels and membrane transporters belonging to the SLC and ABC superfamilies. Indeed, membrane transporter expression in the BBB is less redundant than in other parts of the body. Therefore, any alteration to one of these proteins may pose a threat to the brain. The fifth member of the SLC7 family, which is expressed at the BBB has been the subject of much research over the years. SLC7A5, also known as LAT1, is a plasma membrane transporter of essential amino acids, whose role in brain development is well recognised. The protein is expressed in the membranes of BBB vessels, neurons, and microglia, creating a connection between different areas of the human brain. LAT1 received significant attention in the context of brain tumor treatment, particularly for glioblastoma multiforme, a malignancy with a poor prognosis characterised by fatal relapses. Since several drugs are also substrates of LAT1, its expression at the BBB could be exploited to deliver drugs that target brain diseases. This review describes the functional, structural, and regulatory features of LAT1, focusing on pharmacology in the context of brain homeostasis.
{"title":"Crossing the Borders: the amino acid transporter LAT1 (SLC7A5) in the Blood-Brain Barrier","authors":"Mariafrancesca Scalise , Raffaella Scanga , Lara Console , Michele Galluccio , Flaviana Marzano , Andrea Magrì , Lorena Pochini , Cesare Indiveri","doi":"10.1016/j.neuint.2025.106070","DOIUrl":"10.1016/j.neuint.2025.106070","url":null,"abstract":"<div><div>The blood-brain barrier is an anatomical structure responsible for controlling the flux of nutrients, metabolites, and xenobiotics into and out of the brain. This fundamental function is carried out through the coordinated action of specific ion channels and membrane transporters belonging to the SLC and ABC superfamilies. Indeed, membrane transporter expression in the BBB is less redundant than in other parts of the body. Therefore, any alteration to one of these proteins may pose a threat to the brain. The fifth member of the SLC7 family, which is expressed at the BBB has been the subject of much research over the years. SLC7A5, also known as LAT1, is a plasma membrane transporter of essential amino acids, whose role in brain development is well recognised. The protein is expressed in the membranes of BBB vessels, neurons, and microglia, creating a connection between different areas of the human brain. LAT1 received significant attention in the context of brain tumor treatment, particularly for glioblastoma multiforme, a malignancy with a poor prognosis characterised by fatal relapses. Since several drugs are also substrates of LAT1, its expression at the BBB could be exploited to deliver drugs that target brain diseases. This review describes the functional, structural, and regulatory features of LAT1, focusing on pharmacology in the context of brain homeostasis.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106070"},"PeriodicalIF":4.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257022","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}
Pub Date : 2025-10-08DOI: 10.1016/j.neuint.2025.106067
Shuangyin Xia , Kai Chen , Xin Li , Dingquan Zou , Meng Wang , Yaping Wang
Trigeminal neuralgia (TN) is the most common type of cranial neuralgia. Currently, there remains a significant gap in the availability of effective and safe treatment options in clinical practice. Transdifferentiation of proliferating activated astrocytes into inhibitory neurons is a potential therapeutic strategy for central nervous system diseases. GABAergic neurons are one of the most type of prevalent inhibitory neurons. This study aims to reprogram proliferating astrocytes in the spinal trigeminal subnucleus caudalis (SpVc) into GABAergic neurons, could improve neuronal excitation-inhibition balance, alleviate pain, which serve as a potential treatment for trigeminal neuralgia. A chronic constriction injury of the distal infraorbital nerve (CCI-dION) was induced in the infraorbital branch of the trigeminal nerve to create a rat model of TN. Adeno-associated viruses were used to overexpress transcription factors Sox2 and Mash1 in astrocytes. The changes in astrocytes and GABAergic neurons in the SpVc region were detected by immunofluorescence, Western blotting, qPCR, and electron microscopy. The mechanical pain threshold testing was used to assess rat TN. In the SpVc region of CCI-dION rats, astrocytes showed proliferation and activation, and the number of GABAergic neurons decreased significantly. Overexpressing Sox2 and Mash1 in astrocytes led to a significant transdifferentiation into GABAergic neurons, which − improved the mechanical pain threshold in CCI-dION rats. Furthermore, fluorocitrate-mediated astrocyte deactivation abolished both the neuronal reprogramming and the analgesic effects, underscoring the essential role of astrocytes in this process. These findings suggest that overexpressing Sox2 and Mash1 in astrocytes led to a significant transdifferentiation into GABAergic neurons, which significantly improved the mechanical pain threshold in CCI-dION rats. Thus, this approach has the potential to provide a new treatment for TN.
{"title":"Reprogramming activated astrocytes into GABAergic neurons to treat trigeminal neuralgia","authors":"Shuangyin Xia , Kai Chen , Xin Li , Dingquan Zou , Meng Wang , Yaping Wang","doi":"10.1016/j.neuint.2025.106067","DOIUrl":"10.1016/j.neuint.2025.106067","url":null,"abstract":"<div><div>Trigeminal neuralgia (TN) is the most common type of cranial neuralgia. Currently, there remains a significant gap in the availability of effective and safe treatment options in clinical practice. Transdifferentiation of proliferating activated astrocytes into inhibitory neurons is a potential therapeutic strategy for central nervous system diseases. GABAergic neurons are one of the most type of prevalent inhibitory neurons. This study aims to reprogram proliferating astrocytes in the spinal trigeminal subnucleus caudalis (SpVc) into GABAergic neurons, could improve neuronal excitation-inhibition balance, alleviate pain, which serve as a potential treatment for trigeminal neuralgia. A chronic constriction injury of the distal infraorbital nerve (CCI-dION) was induced in the infraorbital branch of the trigeminal nerve to create a rat model of TN. Adeno-associated viruses were used to overexpress transcription factors <em>Sox2</em> and <em>Mash1</em> in astrocytes. The changes in astrocytes and GABAergic neurons in the SpVc region were detected by immunofluorescence, Western blotting, qPCR, and electron microscopy. The mechanical pain threshold testing was used to assess rat TN. In the SpVc region of CCI-dION rats, astrocytes showed proliferation and activation, and the number of GABAergic neurons decreased significantly. Overexpressing <em>Sox2</em> and <em>Mash1</em> in astrocytes led to a significant transdifferentiation into GABAergic neurons, which − improved the mechanical pain threshold in CCI-dION rats. Furthermore, fluorocitrate-mediated astrocyte deactivation abolished both the neuronal reprogramming and the analgesic effects, underscoring the essential role of astrocytes in this process. These findings suggest that overexpressing <em>Sox2</em> and <em>Mash1</em> in astrocytes led to a significant transdifferentiation into GABAergic neurons, which significantly improved the mechanical pain threshold in CCI-dION rats. Thus, this approach has the potential to provide a new treatment for TN.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106067"},"PeriodicalIF":4.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273342","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}
Pub Date : 2025-10-06DOI: 10.1016/j.neuint.2025.106069
Ling Gao , Xiaobin Zheng , Cong Tan , Li Peng , Chuang Wang , Zhongtao Zheng , Jiangli Han , Jian Wang , Zhao Yang , Weiming Chen
Background
Intracerebral hemorrhage (ICH) is a major cause of secondary brain injury (SBI), which results in severe neurological deficits and poor clinical outcomes. Elevated serum lactate levels have been associated with unfavorable outcome in ICH patients. However, the role of lactate in ICH-induced SBI remain poorly understood.
Method
An autologous blood injection mouse model of ICH and lactate-treated C8D1A cells were employed as the in vivo and in vitro models, respectively. The establishment of ICH model was validated by behavior tests, and brain injury was assessed by H&E and Nissel staining. qRT-PCR, Western blot and IHC analysis were used to detect the expression of key molecules. Immunofluorescent (IF) staining was employed to evaluate astrocyte activation. Pro-inflammatory cytokine release was monitored by ELISA assay. The interaction between H3K18la and METTL3 was assessed by ChIP assay, and the association between METTL3 and LCN2 mRNA was assessed by RNA immunoprecipitation (RIP) assay.
Results
The levels of lactate, METTL3 and LCN2 are elevated in ICH model in mice. The inhibition of lactate decreased METTL3 expression and alleviated ICH-induced SBI. Mechanistically, histone H3K18 lactylation was associated with the upregulated levels of METTL3 and m6A in mouse brains. METTL3 regulated the m6A modification of LCN2 and upregulated its expression. In ICH mice, silencing of LCN2 inhibited A1 astrocyte activation. Histone lactylation-modulated LCN2 m6A modification is involved in astrocyte activation and the regulation of SBI in ICH mice.
Conclusion
These results suggested a mechanism whereby histone lactylation is implicated in the activation of A1 astrocytes through METTL3-mediated LCN2 m6A modification.
{"title":"Histone lactylation is associated with METTL3-dependent LCN2 m6A modification and astrocyte activation after intracerebral hemorrhage","authors":"Ling Gao , Xiaobin Zheng , Cong Tan , Li Peng , Chuang Wang , Zhongtao Zheng , Jiangli Han , Jian Wang , Zhao Yang , Weiming Chen","doi":"10.1016/j.neuint.2025.106069","DOIUrl":"10.1016/j.neuint.2025.106069","url":null,"abstract":"<div><h3>Background</h3><div>Intracerebral hemorrhage (ICH) is a major cause of secondary brain injury (SBI), which results in severe neurological deficits and poor clinical outcomes. Elevated serum lactate levels have been associated with unfavorable outcome in ICH patients. However, the role of lactate in ICH-induced SBI remain poorly understood.</div></div><div><h3>Method</h3><div>An autologous blood injection mouse model of ICH and lactate-treated C8D1A cells were employed as the <em>in vivo</em> and <em>in vitro</em> models, respectively. The establishment of ICH model was validated by behavior tests, and brain injury was assessed by H&E and Nissel staining. qRT-PCR, Western blot and IHC analysis were used to detect the expression of key molecules. Immunofluorescent (IF) staining was employed to evaluate astrocyte activation. Pro-inflammatory cytokine release was monitored by ELISA assay. The interaction between H3K18la and METTL3 was assessed by ChIP assay, and the association between METTL3 and LCN2 mRNA was assessed by RNA immunoprecipitation (RIP) assay.</div></div><div><h3>Results</h3><div>The levels of lactate, METTL3 and LCN2 are elevated in ICH model in mice. The inhibition of lactate decreased METTL3 expression and alleviated ICH-induced SBI. Mechanistically, histone H3K18 lactylation was associated with the upregulated levels of METTL3 and m<sup>6</sup>A in mouse brains. METTL3 regulated the m<sup>6</sup>A modification of LCN2 and upregulated its expression. In ICH mice, silencing of LCN2 inhibited A1 astrocyte activation. Histone lactylation-modulated LCN2 m<sup>6</sup>A modification is involved in astrocyte activation and the regulation of SBI in ICH mice.</div></div><div><h3>Conclusion</h3><div>These results suggested a mechanism whereby histone lactylation is implicated in the activation of A1 astrocytes through METTL3-mediated LCN2 m<sup>6</sup>A modification.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106069"},"PeriodicalIF":4.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249159","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}
Pub Date : 2025-10-04DOI: 10.1016/j.neuint.2025.106062
Cristina Benatti , Alessandra Roggeri , Ylenia Toscano , Veronica Torre , Nicoletta Brunello , Fabio Tascedda , Johanna Maria Catharina Blom , Anna Pittaluga
GABA dictates the efficiency of synaptic connection, influencing its developmental complexity, but its role is tuned by developmental sex differences which affect the efficiency of its innervation. We investigated the efficiency of mechanisms of GABA storage and exocytosis in hippocampal terminals of male and female mice during the juvenile period (PND21), adolescence (PND36) or adulthood (PND90). The expression of mRNA encoding for the presynaptic GABA transporter type 1, (GAT1) and the vesicular GABA transporter (VGAT1) was analysed. A significant scaling-down in the GAT1 mRNA levels (SLC6A1) was detected at PND21 in both sexes until adulthood, while the SLC32A1-VGAT mRNA level was conserved. We also analysed the density of GAT1 and VGAT proteins. Western blot analysis unveiled the presence of a monomeric and an oligomeric form of GAT1. The density of the monomeric form was conserved at the different stages of development in both sexes. Differently, the oligomeric assembly was significantly overexpressed in hippocampal synaptosomal lysates from PND21 male and female mice, but recovered at PND36. VGAT density was largely conserved in PND21 and PND36 male hippocampal synaptosomal lysates when compared to adult particles, but significantly lower in PND21 female particles. Notably, these changes are consistent and support the altered vesicular storage of newly taken-up [3H]GABA detected in PND21 male and female hippocampal synaptosomes as well as the different responsiveness of GABAergic male and female synaptosomes to increasing depolarizing stimuli (12, 20 and 30 mM KCl-enriched solutions) measured as efficiency of the [3H]GABA exocytosis. Interstingly, an acute LPS treatment affects the efficiency of GABA exocytosis at PND36 in a sex-dependent manner. These results add new knowledge on the role of GABA as effector of central inhibitory plasticity at the early stage of development and its relevance in dimorphic adaptation in physio pathological conditions.
{"title":"Differences in presynaptic hippocampal GABAergic terminals at the early stage of life in female and male mice: effect of an acute early inflammatory challenge","authors":"Cristina Benatti , Alessandra Roggeri , Ylenia Toscano , Veronica Torre , Nicoletta Brunello , Fabio Tascedda , Johanna Maria Catharina Blom , Anna Pittaluga","doi":"10.1016/j.neuint.2025.106062","DOIUrl":"10.1016/j.neuint.2025.106062","url":null,"abstract":"<div><div>GABA dictates the efficiency of synaptic connection, influencing its developmental complexity, but its role is tuned by developmental sex differences which affect the efficiency of its innervation. We investigated the efficiency of mechanisms of GABA storage and exocytosis in hippocampal terminals of male and female mice during the juvenile period (PND21), adolescence (PND36) or adulthood (PND90). The expression of mRNA encoding for the presynaptic GABA transporter type 1, (GAT1) and the vesicular GABA transporter (VGAT1) was analysed. A significant scaling-down in the GAT1 mRNA levels (SLC6A1) was detected at PND21 in both sexes until adulthood, while the SLC32A1-VGAT mRNA level was conserved. We also analysed the density of GAT1 and VGAT proteins. Western blot analysis unveiled the presence of a monomeric and an oligomeric form of GAT1. The density of the monomeric form was conserved at the different stages of development in both sexes. Differently, the oligomeric assembly was significantly overexpressed in hippocampal synaptosomal lysates from PND21 male and female mice, but recovered at PND36. VGAT density was largely conserved in PND21 and PND36 male hippocampal synaptosomal lysates when compared to adult particles, but significantly lower in PND21 female particles. Notably, these changes are consistent and support the altered vesicular storage of newly taken-up [<sup>3</sup>H]GABA detected in PND21 male and female hippocampal synaptosomes as well as the different responsiveness of GABAergic male and female synaptosomes to increasing depolarizing stimuli (12, 20 and 30 mM KCl-enriched solutions) measured as efficiency of the [<sup>3</sup>H]GABA exocytosis. Interstingly, an acute LPS treatment affects the efficiency of GABA exocytosis at PND36 in a sex-dependent manner. These results add new knowledge on the role of GABA as effector of central inhibitory plasticity at the early stage of development and its relevance in dimorphic adaptation in physio pathological conditions.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106062"},"PeriodicalIF":4.0,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237879","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}
Pub Date : 2025-10-04DOI: 10.1016/j.neuint.2025.106068
Zhang Piao , Zhu Baoyu , Feng Jiezhu , Liang Xiaomei , Huang Peiting , He Chentao , Deng Yiyu , Lu Jiahong , Wang Lijuan , Zhang Yuhu
This study explores whether Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) regulates the distinct disease-related microglia (DAM) phenotype and exerts a protective role in cognitive impairment in Parkinson's disease (PD). Adeno-associated virus carrying TREM2 shRNA (AAV-TREM2-shRNA) was injected into the bilateral hippocampus of the A53T α-Synuclein (α-Syn) transgenic PD mouse model; Additionally, lentivirus was transduced into BV2 microglial cells to knock out the expression of TREM2, which were subsequently stimulated with α-Syn preformed fibrils (PFF). Furthermore, cognitive status of mice, α-Syn aggregation, microglia status, expression of inflammatory factors, pro-inflammatory and anti-inflammatory DAM markers, MAPK and NF- κB pathway activation status and neuron apoptosis were evaluated. TREM2 deficiency induced cognitive impairment in A53T α-Syn PD mice by decreased performance in the novel objective recognition and Morris water maze tests. TREM2 knockdown resulted in synaptic loss, microglial activation, increased inflammatory factors, and MAPK and NF- κB pathway activation in the hippocampus of mice. In vitro, TREM2 deficiency exacerbated the inflammatory response of BV2 cells stimulated by α-Syn PFF by inhibiting anti-inflammatory DAM, and promoting neuronal apoptosis and Ser129-phosphorylation of α-Syn. TREM2 knockdown also promoted pro-inflammatory DAM activation and increased inflammatory factors expression via the ERK1/2 signaling pathway. Our findings suggest that TREM2 plays a protective role in cognitive impairment and promotes anti-inflammatory DAM activation via the ERK1/2 signaling pathway in PD mice, providing novel insight into the immunopathogenesis of cognitive impairments in PD.
{"title":"TREM2 deficiency aggravates neuroinflammatory response and cognitive impairment via disease-associated microglia in Parkinson's disease models","authors":"Zhang Piao , Zhu Baoyu , Feng Jiezhu , Liang Xiaomei , Huang Peiting , He Chentao , Deng Yiyu , Lu Jiahong , Wang Lijuan , Zhang Yuhu","doi":"10.1016/j.neuint.2025.106068","DOIUrl":"10.1016/j.neuint.2025.106068","url":null,"abstract":"<div><div>This study explores whether Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) regulates the distinct disease-related microglia (DAM) phenotype and exerts a protective role in cognitive impairment in Parkinson's disease (PD). Adeno-associated virus carrying TREM2 shRNA (AAV-TREM2-shRNA) was injected into the bilateral hippocampus of the A53T α-Synuclein (α-Syn) transgenic PD mouse model; Additionally, lentivirus was transduced into BV2 microglial cells to knock out the expression of TREM2, which were subsequently stimulated with α-Syn preformed fibrils (PFF). Furthermore, cognitive status of mice, α-Syn aggregation, microglia status, expression of inflammatory factors, pro-inflammatory and anti-inflammatory DAM markers, MAPK and NF- κB pathway activation status and neuron apoptosis were evaluated. TREM2 deficiency induced cognitive impairment in A53T α-Syn PD mice by decreased performance in the novel objective recognition and Morris water maze tests. TREM2 knockdown resulted in synaptic loss, microglial activation, increased inflammatory factors, and MAPK and NF- κB pathway activation in the hippocampus of mice. In vitro, TREM2 deficiency exacerbated the inflammatory response of BV2 cells stimulated by α-Syn PFF by inhibiting anti-inflammatory DAM, and promoting neuronal apoptosis and Ser129-phosphorylation of α-Syn. TREM2 knockdown also promoted pro-inflammatory DAM activation and increased inflammatory factors expression via the ERK1/2 signaling pathway. Our findings suggest that TREM2 plays a protective role in cognitive impairment and promotes anti-inflammatory DAM activation via the ERK1/2 signaling pathway in PD mice, providing novel insight into the immunopathogenesis of cognitive impairments in PD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"191 ","pages":"Article 106068"},"PeriodicalIF":4.0,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231095","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}
Pub Date : 2025-10-02DOI: 10.1016/j.neuint.2025.106064
Niraj Lodhi , Lauren Powell , Jay S. Schneider
Among different RNA methylations, N6-methyladenosine (m6A) is the most abundant in the brain and determines the fate of RNA through reversible processes using methyltransferases, demethylases, and methyl-binding proteins. The reversibility of m6A is an emerging regulatory mechanism for gene expression, regulating many aspects of RNA metabolism and influencing learning and memory processes. Global m6A profiles are dynamically modified via the activity of various writers, readers, and erasers. However, m6A alterations from exposure to heavy metals, including the metals lead (Pb), cadmium (Cd), cobalt (Co), and manganese (Mn) and the metalloid arsenic (As), and the impact on brain function, are not fully understood. This paper reviews recent work that may begin to shed light on how heavy metal exposures may affect m6A methylation and how this might impact central nervous system functioning.
{"title":"Functional effects of heavy metal exposures on N6-methyladenosine (m6A) methylation and other Epitranscriptomic modifications in the central nervous system","authors":"Niraj Lodhi , Lauren Powell , Jay S. Schneider","doi":"10.1016/j.neuint.2025.106064","DOIUrl":"10.1016/j.neuint.2025.106064","url":null,"abstract":"<div><div>Among different RNA methylations, N6-methyladenosine (m6A) is the most abundant in the brain and determines the fate of RNA through reversible processes using methyltransferases, demethylases, and methyl-binding proteins. The reversibility of m6A is an emerging regulatory mechanism for gene expression, regulating many aspects of RNA metabolism and influencing learning and memory processes. Global m6A profiles are dynamically modified via the activity of various writers, readers, and erasers. However, m6A alterations from exposure to heavy metals, including the metals lead (Pb), cadmium (Cd), cobalt (Co), and manganese (Mn) and the metalloid arsenic (As), and the impact on brain function, are not fully understood. This paper reviews recent work that may begin to shed light on how heavy metal exposures may affect m6A methylation and how this might impact central nervous system functioning.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106064"},"PeriodicalIF":4.0,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228432","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}
Pub Date : 2025-10-02DOI: 10.1016/j.neuint.2025.106065
Zehua Tao , Xinyu Zhang , Jian Chen , Jing Hu , Suhua Wang , Guangwei Xing , Ngwa Adeline Ngeng , Abdul Malik , Kwaku Appiah-Kubi , Marcelo Farina , Anatoly V. Skalny , Alexey A. Tinkov , Michael Aschner , Bobo Yang , Rongzhu Lu
Manganese (Mn), an essential trace element for physiological functions, can induce neurotoxicity through iron-dependent oxidative stress mechanisms when present in excess. This study reveals that Mn triggers ferroptosis in neural cells via nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. Using in vivo (Mn-exposed mice) and in vitro (hippocampal HT22 cells) models, we demonstrated that Mn exposure disrupts iron homeostasis, elevating brain iron accumulation and downregulating ferroptosis-protective proteins (SLC7A11 and GPX4). The ferroptosis inhibitor ferrostatin-1 effectively counteracted Mn-induced cell death, whereas the extracellular iron chelator deferoxamine showed limited protection. Crucially, NCOA4 knockdown significantly mitigated Mn-induced iron overload and cell viability loss, outperforming deferoxamine. These findings establish ferritinophagy as a central mechanism in Mn neurotoxicity and highlight the therapeutic potential of targeting intracellular iron regulation over extracellular chelation. Our work provides a mechanistic foundation for developing interventions against Mn-associated neurodegenerative disorders.
{"title":"Manganese stimulates ferroptosis to trigger neurotoxicity in mice and HT22 cells: the role of NCOA4-mediated ferritinophagy","authors":"Zehua Tao , Xinyu Zhang , Jian Chen , Jing Hu , Suhua Wang , Guangwei Xing , Ngwa Adeline Ngeng , Abdul Malik , Kwaku Appiah-Kubi , Marcelo Farina , Anatoly V. Skalny , Alexey A. Tinkov , Michael Aschner , Bobo Yang , Rongzhu Lu","doi":"10.1016/j.neuint.2025.106065","DOIUrl":"10.1016/j.neuint.2025.106065","url":null,"abstract":"<div><div>Manganese (Mn), an essential trace element for physiological functions, can induce neurotoxicity through iron-dependent oxidative stress mechanisms when present in excess. This study reveals that Mn triggers ferroptosis in neural cells via nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. Using <em>in vivo</em> (Mn-exposed mice) and <em>in vitro</em> (hippocampal HT22 cells) models, we demonstrated that Mn exposure disrupts iron homeostasis, elevating brain iron accumulation and downregulating ferroptosis-protective proteins (SLC7A11 and GPX4). The ferroptosis inhibitor ferrostatin-1 effectively counteracted Mn-induced cell death, whereas the extracellular iron chelator deferoxamine showed limited protection. Crucially, NCOA4 knockdown significantly mitigated Mn-induced iron overload and cell viability loss, outperforming deferoxamine. These findings establish ferritinophagy as a central mechanism in Mn neurotoxicity and highlight the therapeutic potential of targeting intracellular iron regulation over extracellular chelation. Our work provides a mechanistic foundation for developing interventions against Mn-associated neurodegenerative disorders.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106065"},"PeriodicalIF":4.0,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145216808","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}
Ferroptosis constitutes a critical pathological mechanism in cerebral ischemia-reperfusion injury (CI/RI), significantly influencing neurological outcomes. While dual specificity phosphatase 1 (DUSP1) demonstrates neuroprotective effects against CI/RI, its regulatory role in ferroptosis remains to be elucidated. This study systematically investigated the therapeutic potential of DUSP1 through ferroptosis modulation in both in vitro and in vivo models. Using oxygen-glucose deprivation/reoxygenation (OGD/R)-treated PC12 cells with either DUSP1 overexpression or knockdown, we comprehensively assessed ferroptosis parameters including cell viability, malondialdehyde content, glutathione levels, intracellular iron concentration, reactive oxygen species accumulation, and expression of key ferroptosis-related proteins. In middle cerebral artery occlusion/reperfusion (MCAO/R) rat models, pharmacological inhibition of DUSP1 was employed to evaluate its impact on cerebral infarction volume, neurological deficits, histopathological changes, and ferroptosis biomarkers. Mechanistic studies incorporated the p38 mitogen-activated protein kinase pathway inhibitor adezmapimod. Our results demonstrated that (1) ferroptosis was significantly induced in both the OGD/R and MCAO/R models, accompanied by upregulated DUSP1 expression; (2) DUSP1 overexpression attenuated ferroptosis and ameliorated CI/RI, whereas genetic knockdown exacerbated these pathological processes; (3) pharmacological inhibition of DUSP1 aggravated cerebral injury and ferroptosis markers in MCAO/R rats; and (4) adezmapimod treatment effectively rescued ferroptosis progression in DUSP1-deficient cells by restoring glutathione peroxidase 4 and ferroportin expression while downregulating transferrin receptor and Ferritin Heavy Chain levels. These findings establish that DUSP1 confers neuroprotection against CI/RI through p38-mediated ferroptosis regulation, suggesting its promise as a novel therapeutic target for ischemic stroke.
{"title":"DUSP1-mediated suppression of p38 MAPK signaling pathway reduces ferroptosis in cerebral ischemia-reperfusion injury.","authors":"Shuyin Ma, Xiaodong Zhang, Jiaxin Fan, Mengying Chen, Qingling Yao, Nan Zhang, Kaili Shi, Minyu Duan, Han Yang, Tiantian Gao, Xiaodong Ma, Jingyi Wang, Weina Li, Chuxiao Zhou, Shuqin Zhan","doi":"10.1016/j.neuint.2025.106024","DOIUrl":"10.1016/j.neuint.2025.106024","url":null,"abstract":"<p><p>Ferroptosis constitutes a critical pathological mechanism in cerebral ischemia-reperfusion injury (CI/RI), significantly influencing neurological outcomes. While dual specificity phosphatase 1 (DUSP1) demonstrates neuroprotective effects against CI/RI, its regulatory role in ferroptosis remains to be elucidated. This study systematically investigated the therapeutic potential of DUSP1 through ferroptosis modulation in both in vitro and in vivo models. Using oxygen-glucose deprivation/reoxygenation (OGD/R)-treated PC12 cells with either DUSP1 overexpression or knockdown, we comprehensively assessed ferroptosis parameters including cell viability, malondialdehyde content, glutathione levels, intracellular iron concentration, reactive oxygen species accumulation, and expression of key ferroptosis-related proteins. In middle cerebral artery occlusion/reperfusion (MCAO/R) rat models, pharmacological inhibition of DUSP1 was employed to evaluate its impact on cerebral infarction volume, neurological deficits, histopathological changes, and ferroptosis biomarkers. Mechanistic studies incorporated the p38 mitogen-activated protein kinase pathway inhibitor adezmapimod. Our results demonstrated that (1) ferroptosis was significantly induced in both the OGD/R and MCAO/R models, accompanied by upregulated DUSP1 expression; (2) DUSP1 overexpression attenuated ferroptosis and ameliorated CI/RI, whereas genetic knockdown exacerbated these pathological processes; (3) pharmacological inhibition of DUSP1 aggravated cerebral injury and ferroptosis markers in MCAO/R rats; and (4) adezmapimod treatment effectively rescued ferroptosis progression in DUSP1-deficient cells by restoring glutathione peroxidase 4 and ferroportin expression while downregulating transferrin receptor and Ferritin Heavy Chain levels. These findings establish that DUSP1 confers neuroprotection against CI/RI through p38-mediated ferroptosis regulation, suggesting its promise as a novel therapeutic target for ischemic stroke.</p>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":" ","pages":"106024"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768181","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}
Pub Date : 2025-09-30DOI: 10.1016/j.neuint.2025.106066
Wenshuang Li , Baomiao Ma , Xiang Tian , Qi Xiong , Mengqi Zhou , Wei Liu , Xiji Shu
Aberrant phosphorylation of the Tau protein represents a critical event in the pathogenesis of Alzheimer's disease (AD); however, therapeutic interventions specifically targeting this modification remain limited. Therefore, a thorough understanding of the molecular mechanisms underlying Tau hyperphosphorylation is essential for the development of effective preventive and therapeutic strategies against AD. The RNA-binding protein MUSASHI1 (MSI1) is recognized for its significant role in neurodevelopment, and previous studies have reported its dysregulated overexpression in the brains of AD patients. In the current investigation, we demonstrate that MSI1 expression progressively increases in parallel with the advancement of Tau pathology in P301S transgenic mouse models. Furthermore, our findings suggest that MSI1 activates the p38 mitogen-activated protein kinase (MAPK) signaling pathway, thereby promoting Tau phosphorylation. Additionally, we have identified two microtubule-associated proteins as novel potential interaction partners of MSI1 within neuronal cells. Collectively, these results reveal a previously uncharacterized mechanism that may contribute to aberrant Tau phosphorylation in AD, offering new directions for future research in this field.
{"title":"MUSASHI1 promotes tau phosphorylation by activating the p38 MAPK pathway","authors":"Wenshuang Li , Baomiao Ma , Xiang Tian , Qi Xiong , Mengqi Zhou , Wei Liu , Xiji Shu","doi":"10.1016/j.neuint.2025.106066","DOIUrl":"10.1016/j.neuint.2025.106066","url":null,"abstract":"<div><div>Aberrant phosphorylation of the Tau protein represents a critical event in the pathogenesis of Alzheimer's disease (AD); however, therapeutic interventions specifically targeting this modification remain limited. Therefore, a thorough understanding of the molecular mechanisms underlying Tau hyperphosphorylation is essential for the development of effective preventive and therapeutic strategies against AD. The RNA-binding protein MUSASHI1 (MSI1) is recognized for its significant role in neurodevelopment, and previous studies have reported its dysregulated overexpression in the brains of AD patients. In the current investigation, we demonstrate that MSI1 expression progressively increases in parallel with the advancement of Tau pathology in P301S transgenic mouse models. Furthermore, our findings suggest that MSI1 activates the p38 mitogen-activated protein kinase (MAPK) signaling pathway, thereby promoting Tau phosphorylation. Additionally, we have identified two microtubule-associated proteins as novel potential interaction partners of MSI1 within neuronal cells. Collectively, these results reveal a previously uncharacterized mechanism that may contribute to aberrant Tau phosphorylation in AD, offering new directions for future research in this field.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106066"},"PeriodicalIF":4.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211323","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}
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