Pub Date : 2026-01-05DOI: 10.1016/j.neuint.2026.106115
Antero Salminen
The primary cause of Alzheimer's disease (AD) is still unknown although genetic studies have identified several risk genes and significant alterations in the chromatin landscape. These genetic changes are associated with neuroinflammation and clear signs of neurodegeneration and cognitive impairment. While the redox-sensitive high mobility group box 1 (HMGB1) protein is a chromatin binding chaperone which maintains the integrity of chromatin, it is also a stress-induced alarmin factor released from the nucleus and subsequently secreted into extracellular space where it is a major inducer of inflammatory responses. There is abundant evidence that HMGB1 is a multifunctional regulator of AD pathology because it can (i) stimulate neuroinflammatory responses, (ii) disrupt the blood-brain barrier, (iii) inhibit microglial clearance of β-amyloid deposits, (iv) trigger cellular senescence and induce cell death, and (v) stimulate synapse loss and cognitive impairment. Experiments with transgenic AD mice have revealed that a release of HMGB1 from nuclei and its secretion promoted neuroinflammation and aggravated AD pathology. Conversely, it is known that the inhibition of HMGB1 expression or its nuclear release attenuated neuroinflammation and delayed the pathological changes in transgenic AD mice. Given that there are many drugs which can inhibit HMGB1-induced inflammatory states, it seems that HMGB1 is a promising therapeutic target to suppress AD pathogenesis.
{"title":"Redox-sensitive high mobility group box 1 (HMGB1) protein is a multipotent regulator in the pathogenesis of Alzheimer's disease","authors":"Antero Salminen","doi":"10.1016/j.neuint.2026.106115","DOIUrl":"10.1016/j.neuint.2026.106115","url":null,"abstract":"<div><div>The primary cause of Alzheimer's disease (AD) is still unknown although genetic studies have identified several risk genes and significant alterations in the chromatin landscape. These genetic changes are associated with neuroinflammation and clear signs of neurodegeneration and cognitive impairment. While the redox-sensitive high mobility group box 1 (HMGB1) protein is a chromatin binding chaperone which maintains the integrity of chromatin, it is also a stress-induced alarmin factor released from the nucleus and subsequently secreted into extracellular space where it is a major inducer of inflammatory responses. There is abundant evidence that HMGB1 is a multifunctional regulator of AD pathology because it can (i) stimulate neuroinflammatory responses, (ii) disrupt the blood-brain barrier, (iii) inhibit microglial clearance of β-amyloid deposits, (iv) trigger cellular senescence and induce cell death, and (v) stimulate synapse loss and cognitive impairment. Experiments with transgenic AD mice have revealed that a release of HMGB1 from nuclei and its secretion promoted neuroinflammation and aggravated AD pathology. Conversely, it is known that the inhibition of HMGB1 expression or its nuclear release attenuated neuroinflammation and delayed the pathological changes in transgenic AD mice. Given that there are many drugs which can inhibit HMGB1-induced inflammatory states, it seems that HMGB1 is a promising therapeutic target to suppress AD pathogenesis.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"193 ","pages":"Article 106115"},"PeriodicalIF":4.0,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145916563","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 : 2026-01-01DOI: 10.1016/j.neuint.2025.106108
Zuohui Zhang, Wen Wen, Hong Lin, Di Hu, Hui Li, Jia Luo
Prenatal alcohol exposure (PAE) can lead to fetal alcohol spectrum disorder (FASD), a condition marked by developmental brain defects that result in neurobehavioral and cognitive impairments. However, the underlying molecular mechanisms remain poorly understood. Brain development is a highly regulated process, with neurogenesis playing a crucial role. A key stage in this process is neural differentiation, which is essential for proper brain function. This study aims to investigate how alcohol disrupts neural differentiation. NE-4C cells, a neural stem cell line derived from the mouse embryonic brain, were utilized as an in vitro model. As an in vivo model, pregnant mice were exposed to alcohol between gestation days 14 and 16, after which newly formed neurons in the ventricular zone (VZ) were analyzed. To examine the role of endoplasmic reticulum (ER) stress, tunicamycin (TM), and MANF-deficient NE-4C cells were employed. Neural differentiation was assessed using immunofluorescence, immunoblotting and flow cytometry. Alcohol impaired the differentiation of NE-4C cells into neurons and astrocytes without impacting cell migration. It also induced ER stress, preferably activating the PERK pathway. Similarly, ER stress caused by TM and MANF deficiency disrupted neural differentiation and activated PERK. Inhibiting PERK mitigated alcohol-induced impairment of neuronal differentiation. PAE decreased the number of newly formed neurons in the VZ of fetal brain while having little effects on cell survival and proliferation. Inhibiting PERK partially reversed the reduction of new neurons caused by PAE. Thus, alcohol-induced ER stress, particularly PERK activation, may contribute to impaired neurogenesis linked to FASD.
{"title":"Alcohol disrupts neural differentiation through endoplasmic reticulum stress and PERK pathway activation","authors":"Zuohui Zhang, Wen Wen, Hong Lin, Di Hu, Hui Li, Jia Luo","doi":"10.1016/j.neuint.2025.106108","DOIUrl":"10.1016/j.neuint.2025.106108","url":null,"abstract":"<div><div>Prenatal alcohol exposure (PAE) can lead to fetal alcohol spectrum disorder (FASD), a condition marked by developmental brain defects that result in neurobehavioral and cognitive impairments. However, the underlying molecular mechanisms remain poorly understood. Brain development is a highly regulated process, with neurogenesis playing a crucial role. A key stage in this process is neural differentiation, which is essential for proper brain function. This study aims to investigate how alcohol disrupts neural differentiation. NE-4C cells, a neural stem cell line derived from the mouse embryonic brain, were utilized as an <em>in vitro</em> model. As an <em>in vivo</em> model, pregnant mice were exposed to alcohol between gestation days 14 and 16, after which newly formed neurons in the ventricular zone (VZ) were analyzed. To examine the role of endoplasmic reticulum (ER) stress, tunicamycin (TM), and MANF-deficient NE-4C cells were employed. Neural differentiation was assessed using immunofluorescence, immunoblotting and flow cytometry. Alcohol impaired the differentiation of NE-4C cells into neurons and astrocytes without impacting cell migration. It also induced ER stress, preferably activating the PERK pathway. Similarly, ER stress caused by TM and MANF deficiency disrupted neural differentiation and activated PERK. Inhibiting PERK mitigated alcohol-induced impairment of neuronal differentiation. PAE decreased the number of newly formed neurons in the VZ of fetal brain while having little effects on cell survival and proliferation. Inhibiting PERK partially reversed the reduction of new neurons caused by PAE. Thus, alcohol-induced ER stress, particularly PERK activation, may contribute to impaired neurogenesis linked to FASD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106108"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145877444","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 : 2025-12-31DOI: 10.1016/j.neuint.2025.106109
Dandan He , Huajian Zhao , Yong Zhu , Yufei Kou , Tao Liu , Huahai Huang , Haiming Yang , Lihua Zhang , Jingyue Deng , Feng Xu , Qingyong Wang
Purpose
This study aimed to investigate the role of USP53 and its associated signaling pathway associated with USP53 in Alzheimer's disease (AD).
Methods
In vivo experiments were conducted in C57BL/6, 5XFAD, and USP53-knockout 5XFAD (USP53−/−) mice. In vitro 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.
Results
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. In vitro 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.
Conclusion
USP53 promotes the activation of neuroinflammation and worsens learning ability and memory in AD mice, mediated by NOTCH2.
{"title":"USP53 promotes NOTCH2-induced neuroinflammation in Alzheimer's disease","authors":"Dandan He , Huajian Zhao , Yong Zhu , Yufei Kou , Tao Liu , Huahai Huang , Haiming Yang , Lihua Zhang , Jingyue Deng , Feng Xu , 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<sup>−/−</sup>) 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<sup>−/−</sup> 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":"2025-12-31","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}
Pub Date : 2025-12-23DOI: 10.1016/j.neuint.2025.106107
Ming-Shang Pai , Mao-Hsiang Hsiao , Ming-Yi Lee , Hsin Chang , Wei-Che Chiu , Su-Jane Wang
This study examined the effects of butein, a natural chalcone, on glutamate release from rat cortical synaptosomes and elucidated the underlying mechanisms. Using 4-aminopyridine (4-AP) to evoke glutamate releases, we found that butein inhibited evoked glutamate release in a concentration-dependent manner (IC50 = 11.4 μM) without altering basal release. The inhibition required extracellular Ca2+, as it was prevented under Ca2+-free conditions. Butein attenuated 4-AP-induced cytosolic Ca2+ elevation without affecting membrane depolarization. Moreover, the inhibitory effect of butein on evoked glutamate release was prevented by blockade of vesicular glutamate transporters, P/Q-type Ca2+ channels or protein kinase C (PKC), but was unaffected by inhibition of N-type Ca2+ channels, protein kinase A (PKA), Ca2+/calmodulin-dependent kinase II (CaMKII), or mitogen-activated protein kinase (MAPK). Western blot analysis showed that butein suppressed 4-AP-induced phosphorylation of PKC, PKCα, and the downstream substrates myristoylated alanine-rich C-kinase substrate (MARCKS) and synaptosomal-associated protein-25 (SNAP-25). FM1-43 dye release and synaptotagmin 1 antibody (syt1-L ab) uptake assays further demonstrated that butein inhibits exocytotic vesicle release. Collectively, these findings indicate that butein inhibits evoked glutamate release from cortical nerve terminals by reducing P/Q-type Ca2+ channel–dependent Ca2+ influx and subsequently downregulating the PKC-mediated signaling pathways.
{"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 , Mao-Hsiang Hsiao , Ming-Yi Lee , Hsin Chang , Wei-Che Chiu , 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 (IC<sub>50</sub> = 11.4 μM) without altering basal release. The inhibition required extracellular Ca<sup>2+</sup>, as it was prevented under Ca<sup>2+</sup>-free conditions. Butein attenuated 4-AP-induced cytosolic Ca<sup>2+</sup> 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 Ca<sup>2+</sup> channels or protein kinase C (PKC), but was unaffected by inhibition of N-type Ca<sup>2+</sup> channels, protein kinase A (PKA), Ca<sup>2+</sup>/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 Ca<sup>2+</sup> channel–dependent Ca<sup>2+</sup> 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":"2025-12-23","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}
Pub Date : 2025-12-23DOI: 10.1016/j.neuint.2025.106106
Abdulkadir Cidem , Muhammet Oner , Gary Ro-Lin Chang , Chih-Ching Yen , Ke-Rong Chen , Shang-Hsun Yang , Ho Lin , Chuan-Mu Chen
Lactoferrin (LF) is a multifunctional glycoprotein with established roles in non-neuronal cell growth and differentiation and has underexplored potential in neurodevelopment. Here, we investigated bovine lactoferrin (bLF) as a neurotrophic agent, systematically evaluating its effects on neuronal differentiation, morphology, and mitochondrial regulation in PC12 cells. We demonstrated that bLF (50 μg/mL) induces neurite outgrowth comparable to nerve growth factor (NGF) while maintaining >90 % cell viability. Mechanistically, bLF activated TrkA by phosphorylation at Ser490, followed by ERK phosphorylation at Thr202/Tyr204 within 60 min, mirroring canonical NGF signaling. bLF also upregulates p35 (CDK5 activator) and phosphorylates Synapsin-I, driving presynaptic maturation. Structurally predicted to bind TrkA's ligand-binding interface, bLF synergizes with NGF to amplify differentiation outcomes. Furthermore, TMRE staining and AMPK phosphorylation assays revealed that bLF enhances axonal mitochondrial activity, surpassing NGF's effects. These results establish bLF as a multifunctional neurotrophic agent that coordinates TrkA-ERK-p35/CDK5 signaling, synaptic protein activation, and AMPK-driven mitochondrial regulation. Given its safety profile and synergy with endogenous neurotrophic pathways, bLF emerges as a promising candidate for neuroregenerative therapies targeting nerve injury or neurodegeneration.
{"title":"BLF stimulates neuronal differentiation via activation of p35/CDK5 signaling and AMPK-mediated mitochondrial regulation","authors":"Abdulkadir Cidem , Muhammet Oner , Gary Ro-Lin Chang , Chih-Ching Yen , Ke-Rong Chen , Shang-Hsun Yang , Ho Lin , 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 >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":"2025-12-23","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}
Pub Date : 2025-12-15DOI: 10.1016/j.neuint.2025.106105
Bing Fan , YuSheng Liang , TianTian Zhi , Lei Wu , YangXia Wu , Yan Yang , Zhi Xie , Xian Wu
Background
Alzheimer's disease (AD) is the most common type of dementia, characterized by progressive cognitive decline and neuronal damage. Although studies have indicated a link between G-protein coupled receptor 55 (GPR55) and AD-related cognitive impairment, the underlying mechanisms remain unclear. Here, we aim to further investigate the role of GPR55 in the pathogenesis of AD.
Methods
We used viral vectors to knock down GPR55 expression in the hippocampus of normal mice. We also generated GPR55 knockout in AD mice by crossing GPR55−/− mice with APP/PS1 transgenic mice (APP/PS1; GPR55−/−). Behavioral tests were conducted to assess spatial memory deficits in 9-month-old APP/PS1; GPR55−/− mice. We also assessed the amyloid β (Aβ) deposition, glial cell activation, and synaptic protein expression in the hippocampus. In addition, we used AAV9 viruses to overexpress GPR55 in the hippocampus of APP/PS1; GPR55−/− mice to further observe its effect on cognitive function.
Results
Knockdown of GPR55 in the hippocampus induces AD-like pathology, cognitive dysfunction, neuroinflammation, and synaptic plasticity damage in normal mice. This was evidenced by increased hippocampal levels of Aβ and p-Tau, enhanced glial cell activation accompanied by upregulation of proinflammatory cytokines, and aggravated synaptic plasticity damage in the normal mice. Furthermore, knockdown of GPR55 induced the reduction of P-AKT1/2/3/AKT1/2/3 and P-GSK3β/GSK3β, while increasing the expression of P-ERK1/2/ERK1/2 in the hippocampus of normal mice. In addition, GPR55 deficiency exacerbated AD-like pathology and spatial learning and memory deficits in APP/PS1 mice. Conversely, AAV9-mediated overexpression of GPR55 rescued spatial memory impairments in APP/PS1; GPR55−/− mice.
Conclusions
These findings underscore the critical role of GPR55 in AD progression and highlight its potential as a therapeutic target for AD treatment.
{"title":"GPR55 deficiency exacerbates cognitive impairments and Alzheimer's disease-like pathology in mice","authors":"Bing Fan , YuSheng Liang , TianTian Zhi , Lei Wu , YangXia Wu , Yan Yang , Zhi Xie , 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<sup>−/−</sup> mice with APP/PS1 transgenic mice (APP/PS1; GPR55<sup>−/−</sup>). Behavioral tests were conducted to assess spatial memory deficits in 9-month-old APP/PS1; GPR55<sup>−/−</sup> 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<sup>−/−</sup> 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<sup>−/−</sup> 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":"2025-12-15","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}
Pub Date : 2025-12-14DOI: 10.1016/j.neuint.2025.106104
Yi-Wen Huang , Hua-Chen Chan , Jing-Yi Khoo , Mei-Lin Chan , Daniel Bender , Vinoth Kumar Ponnusamy , Abdel Ali Belaidi , Liang-Yin Ke
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, and synaptic loss. Emerging evidence indicates that apolipoprotein E (APOE) polymorphism and dysregulated ceramide metabolism are critical links among these pathogenic processes. Ceramide accumulation in the brain contributes to Aβ generation, tau phosphorylation, and neuronal apoptosis. Elevated ceramide levels have been observed in plasma, cerebrospinal fluid, and peripheral organs such as the liver, reflecting systemic lipid dysregulation. Lipoproteins—particularly low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL)—transport ceramide across the blood–brain barrier, while apoE4 isoforms exacerbate this process by disrupting vascular integrity and lipid homeostasis. In addition, hepatic and gut-derived ceramides may influence neurodegeneration through the liver–gut–brain axis. Therapeutic interventions targeting ceramide synthesis (serine palmitoyltransferase inhibitors), production (neutral sphingomyelinase inhibitors), and the ceramide/sphingosine-1-phosphate (S1P) balance show potential in preclinical models for reducing Aβ pathology, tau aggregation, and neuroinflammation. These findings position ceramide metabolism as a critical mediator of AD pathogenesis and a promising target for diagnosis and treatment. Modulating ceramide and S1P signaling could complement current amyloid- and tau-directed therapies, offering new opportunities for disease modification and early intervention.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是淀粉样蛋白-β (a β)沉积、tau过度磷酸化和突触丧失。新出现的证据表明载脂蛋白E （APOE）多态性和神经酰胺代谢失调是这些致病过程的关键环节。神经酰胺在大脑中的积累有助于Aβ的产生，tau磷酸化和神经元凋亡。在血浆、脑脊液和肝等外周器官中观察到神经酰胺水平升高，反映了全身性脂质失调。脂蛋白——尤其是低密度脂蛋白（LDL）和极低密度脂蛋白（VLDL）——通过血脑屏障运输神经酰胺，而apoE4亚型通过破坏血管完整性和脂质稳态加剧了这一过程。此外，肝和肠源性神经酰胺可能通过肝-肠-脑轴影响神经退行性变。针对神经酰胺合成（丝氨酸棕榈酰基转移酶抑制剂）、产生（中性鞘磷脂酶抑制剂）和神经酰胺/鞘磷脂-1-磷酸（S1P）平衡的治疗干预在临床前模型中显示出减少Aβ病理、tau聚集和神经炎症的潜力。这些发现表明神经酰胺代谢是阿尔茨海默病发病机制的关键介质，也是诊断和治疗的一个有希望的靶点。调节神经酰胺和S1P信号可以补充目前的淀粉样蛋白和tau定向治疗，为疾病改变和早期干预提供新的机会。
{"title":"Assessing the critical role of ceramide in the pathogenesis of Alzheimer's disease and its clinical significance","authors":"Yi-Wen Huang , Hua-Chen Chan , Jing-Yi Khoo , Mei-Lin Chan , Daniel Bender , Vinoth Kumar Ponnusamy , Abdel Ali Belaidi , 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":"2025-12-14","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}
Pub Date : 2025-12-11DOI: 10.1016/j.neuint.2025.106103
Huahua Shi , Yan Zhao
Tauopathies are a group of neurodegenerative disorders characterized by the presence of abnormal aggregates of microtubule associated protein tau in the brain. In the most common tauopathy, Alzheimer's disease (AD), the aggregation of tau is closely linked with synaptic dysfunction and neuronal death, while targeting the aggregation of tau has been demonstrated to have therapeutic potential. Astaxanthin is a carotenoid with neuroprotective function, which has been shown to inhibit Aβ-induced pathology in AD animal and cell models. However, the effects of astaxanthin on tau aggregation and toxicity are much less explored. In this study, we generated a cell model of tauopathy overexpressing the amyloidogenic pro-aggregant tau repeat domains carrying the FTDP-17 mutation ΔK280 in N2a cells (N2a-tau4RDΔK280). It was found that astaxanthin treatment alleviated the cytotoxicity of N2a-tau4RDΔK280 cells while reducing the amount of tau4RDΔK280 aggregates in the cells. Results from the thioflavin T aggregation assay demonstrated that astaxanthin inhibited the aggregation of tau4RDΔK280 in vitro. Further analyses with transmission electron microscopy confirmed that astaxanthin reduced the formation of amyloid fibril structures of tau4RDΔK280 in vitro. Thus, astaxanthin might inhibit the cytotoxicity of N2a-tau4RDΔK280 cells by preventing the formation of tau4RDΔK280 aggregates. Molecular docking simulation analyses revealed that astaxanthin was able to directly interact with tau4RDΔK280 as well as several key aggregation-prone segments of tau protein. In conclusion, our results demonstrated that astaxanthin might exert neuroprotection by inhibiting the formation of tau aggregates via direct interaction with the key aggregation-prone segments.
{"title":"Astaxanthin inhibits the aggregation and cytotoxicity of tau4RDΔK280 via possible interaction with the aggregation-prone segments","authors":"Huahua Shi , Yan Zhao","doi":"10.1016/j.neuint.2025.106103","DOIUrl":"10.1016/j.neuint.2025.106103","url":null,"abstract":"<div><div>Tauopathies are a group of neurodegenerative disorders characterized by the presence of abnormal aggregates of microtubule associated protein tau in the brain. In the most common tauopathy, Alzheimer's disease (AD), the aggregation of tau is closely linked with synaptic dysfunction and neuronal death, while targeting the aggregation of tau has been demonstrated to have therapeutic potential. Astaxanthin is a carotenoid with neuroprotective function, which has been shown to inhibit Aβ-induced pathology in AD animal and cell models. However, the effects of astaxanthin on tau aggregation and toxicity are much less explored. In this study, we generated a cell model of tauopathy overexpressing the amyloidogenic pro-aggregant tau repeat domains carrying the FTDP-17 mutation ΔK280 in N2a cells (N2a-tau<sub>4RD</sub>ΔK280). It was found that astaxanthin treatment alleviated the cytotoxicity of N2a-tau<sub>4RD</sub>ΔK280 cells while reducing the amount of tau<sub>4RD</sub>ΔK280 aggregates in the cells. Results from the thioflavin T aggregation assay demonstrated that astaxanthin inhibited the aggregation of tau<sub>4RD</sub>ΔK280 <em>in vitro</em>. Further analyses with transmission electron microscopy confirmed that astaxanthin reduced the formation of amyloid fibril structures of tau<sub>4RD</sub>ΔK280 <em>in vitro</em>. Thus, astaxanthin might inhibit the cytotoxicity of N2a-tau<sub>4RD</sub>ΔK280 cells by preventing the formation of tau<sub>4RD</sub>ΔK280 aggregates. Molecular docking simulation analyses revealed that astaxanthin was able to directly interact with tau<sub>4RD</sub>ΔK280 as well as several key aggregation-prone segments of tau protein. In conclusion, our results demonstrated that astaxanthin might exert neuroprotection by inhibiting the formation of tau aggregates via direct interaction with the key aggregation-prone segments.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106103"},"PeriodicalIF":4.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145751434","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 : 2025-12-11DOI: 10.1016/j.neuint.2025.106102
Nozomi Tokunaga, Rikako Fujimoto, Yoki Nakamura, Kazue Hisaoka-Nakashima, Norimitsu Morioka
Depression is a major mental illness, and its underlying mechanisms remain unclear. Emerging evidence suggests that astrocytes, which play a crucial role in brain function, may be involved in the pathophysiology of depression. We previously showed that downregulation of astrocytic connexin43 (Cx43) enhances the antidepressant effect of amitriptyline. However, the precise molecular mechanisms underlying this phenomenon remain unknown. In the present study, we investigated the signaling pathways involved in the antidepressant action of amitriptyline using an in vitro model involving Cx43-knockdown astrocytes. We found that amitriptyline potentiated the expression of brain-derived neurotrophic factor (BDNF), a key neurotrophic factor, in Cx43-knockdown astrocytes. This potentiation was mediated by the activation of Gq protein-coupled lysophosphatidic acid (LPA) receptors, a pathway that was sensitized by Cx43 downregulation. We further demonstrated that this signaling cascade involved the activation of Protein Kinase C (PKC) δ and transcription factor NF-κB, but not the conventional BDNF transcription factor CREB. We propose that Cx43 downregulation enhances the antidepressant effect of amitriptyline by specifically engaging the Gq-PKCδ–NF–κB pathway. These findings suggest that Cx43 downregulation in astrocytes, which has been considered a pathological feature of depression, may paradoxically contribute to the therapeutic efficacy of antidepressants by sensitizing a specific signaling pathway. Our study provides new insights into the molecular mechanism of antidepressant action and highlights the potential role of astrocytic Cx43 in modulating therapeutic responses.
{"title":"Tricyclic antidepressant amitriptyline potentiates brain-derived neurotrophic factor expression mediated by PKC delta–NF–kappa B signaling in primary cultured astrocytes with connexin43-knockdown","authors":"Nozomi Tokunaga, Rikako Fujimoto, Yoki Nakamura, Kazue Hisaoka-Nakashima, Norimitsu Morioka","doi":"10.1016/j.neuint.2025.106102","DOIUrl":"10.1016/j.neuint.2025.106102","url":null,"abstract":"<div><div>Depression is a major mental illness, and its underlying mechanisms remain unclear. Emerging evidence suggests that astrocytes, which play a crucial role in brain function, may be involved in the pathophysiology of depression. We previously showed that downregulation of astrocytic connexin43 (Cx43) enhances the antidepressant effect of amitriptyline. However, the precise molecular mechanisms underlying this phenomenon remain unknown. In the present study, we investigated the signaling pathways involved in the antidepressant action of amitriptyline using an <em>in vitro</em> model involving Cx43-knockdown astrocytes. We found that amitriptyline potentiated the expression of brain-derived neurotrophic factor (BDNF), a key neurotrophic factor, in Cx43-knockdown astrocytes. This potentiation was mediated by the activation of Gq protein-coupled lysophosphatidic acid (LPA) receptors, a pathway that was sensitized by Cx43 downregulation. We further demonstrated that this signaling cascade involved the activation of Protein Kinase C (PKC) δ and transcription factor NF-κB, but not the conventional BDNF transcription factor CREB. We propose that Cx43 downregulation enhances the antidepressant effect of amitriptyline by specifically engaging the Gq-PKCδ–NF–κB pathway. These findings suggest that Cx43 downregulation in astrocytes, which has been considered a pathological feature of depression, may paradoxically contribute to the therapeutic efficacy of antidepressants by sensitizing a specific signaling pathway. Our study provides new insights into the molecular mechanism of antidepressant action and highlights the potential role of astrocytic Cx43 in modulating therapeutic responses.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"192 ","pages":"Article 106102"},"PeriodicalIF":4.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145751458","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 : 2025-12-09DOI: 10.1016/j.neuint.2025.106101
Suhong Ye , Qiaolu Xu , Nashwa Amin , Ling Bao , Yang Yang , Irum Naz Abbasi , Marong Fang
Depression is a prevalent and debilitating mental disorder with substantial impacts on global health and socioeconomic costs. Despite various antidepressants targeting monoaminergic neurotransmission, a significant proportion of patients fail to achieve remission with existing treatments. Agomelatine (AGO), as a novel antidepressant, has shown promise in treating depression. However, the neural circuits and molecular mechanisms underlying its therapeutic effects remain largely unknown. This study aimed to investigate the role of GABAergic neural circuits on the antidepressant effects of AGO and elucidate the underlying cellular and molecular mechanisms. A chronic unpredictable mild stress (CUMS) mouse model was used to induce depressive-like behaviors. Genetic manipulation was employed to selectively ablate GABAergic neurons, and the effects of AGO treatment on behavioral performance and neuronal morphology were assessed. Additionally, the expression of synaptic and clock genes was analyzed to explore underlying molecular mechanisms. We found that AGO treatment significantly improved the behavioral performance of CUMS mice and rescued the structural integrity and quantity of central neurons. It regulated the protein expressions of VGAT, VGLUT1, and Gad65 in the brain tissues of CUMS mice. Notably, AGO altered the protein and gene expressions in GABAergic neural circuits across different brain regions. Morphological analysis revealed that AGO improved dendritic spine density and length in neurons in the selective ablation of GABAergic interneurons. The antidepressant effects of AGO involve the modulation of GABAergic neural circuits as a critical but non-exclusive target, alongside the restoration of GABAergic-glutamatergic balance, synaptic function, and clock gene expressions. These findings highlight AGO's potential in normalizing disrupted neuronal function in depression and offer insights into novel multi-target therapeutic strategies.
{"title":"Investigating the role of GABAergic interneurons in the antidepressant-like mechanism of agomelatine","authors":"Suhong Ye , Qiaolu Xu , Nashwa Amin , Ling Bao , Yang Yang , Irum Naz Abbasi , 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":"2025-12-09","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}
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