Neurochemistry international最新文献

{"title":"Targeted Stabilization of Astrocytic Cx43 Gap Junctions Reverses Depression-like Behaviors via Dual Restoration of Syncytial Networks and Glutamatergic Homeostasis.","authors":"Xin-Mu Li, Meng Zhang, Zan Xing, Xue-Ying Yang, Hua-Qing Lai, Yuan-Chun Wang, Hong Jiang, Xu Yan, Shi-Feng Chu, Nai-Hong Chen, Zhen-Zhen Wang","doi":"10.1016/j.neuint.2026.106168","DOIUrl":"https://doi.org/10.1016/j.neuint.2026.106168","url":null,"abstract":"<p><p>Depression, a debilitating global mental disorder affecting millions of people worldwide, is characterized by persistent low mood and anhedonia. Growing evidence identifies astrocyte dysfunction and glutamate metabolism imbalance as core pathological features of this condition. Notably, astrocytic connexin 43 (Cx43) downregulation and subsequent gap junction (GJ) impairment constitute recognized pathological features of depression. However, the development of direct therapeutic strategies targeting Cx43-GJ remains underexplored, representing a significant gap in current antidepressant drug discovery. Here, using integrated in vitro (corticosterone-induced dysfunctional astrocytes) and in vivo (chronic unpredictable stress [CUS]-induced mice) systems, we demonstrate that chronic stress depletes Cx43-GJs, driving astrocyte atrophy, disrupting syncytial network integrity, and dysregulating synaptic glutamate-glutamine cycling. Functional magnetic resonance imaging further revealed widespread impairment of whole-brain functional connectivity in CUS mice, while microRNA sequencing additionally confirmed glutamatergic synaptic dysfunction. Treatment with ZP1609, a selective Cx43-GJ stabilizer that preserves Cx43-GJ functionality without modulating connexin hemichannel activity, ameliorated depressive-like behaviors and specifically restored hippocampus-centered functional connectivity in CUS mice. Mechanistic investigation revealed ZP1609 exerts its effects through dual pathways: (ⅰ) stabilizing Cx43-GJs to maintain intercellular communication and reverse astrocyte structural atrophy, thereby restoring syncytial network integrity; and (ⅱ) normalizing astrocytic glutamate-glutamine cycling to mitigate synaptic excitotoxicity and protect glutamatergic synaptic function. Our findings suggest Cx43-GJ stabilization as a novel therapeutic strategy that simultaneously rectifies astrocyte network failure and glutamatergic synaptic impairment, providing preclinical evidence for Cx43-GJ-targeted antidepressants development.</p>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":" ","pages":"106168"},"PeriodicalIF":4.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurometabolite changes in cingulate cortex regions in healthy Indian population and effect of Bacopa monnieri intervention: a H¹ MRS study.","authors":"Arman Deep Singh, Mukesh Kumar, Swathi Bh, Bhargavi P, Ashwini Godbole, Subash Khushu","doi":"10.1016/j.neuint.2026.106163","DOIUrl":"https://doi.org/10.1016/j.neuint.2026.106163","url":null,"abstract":"<p><p>The present study investigates the age-related neuro-metabolite changes in anterior-cingulate cortex (ACC) and posterior-cingulate cortex (PCC) and their correlation with cognitive performance. The study also probes the impact of formulations of Brahmi (Bacopa monnieri (L.) Wettst.), a well-known nootropic, on neuro-metabolite concentration, cognitive performance and brain health. We performed ¹H MRS from ACC and PCC and neuropsychological test on three cohorts, younger age (25-40 years, n=37), middle age (41-55 years, n=28) and older age group (56-85 years, n= 31). In addition, the subjects with age 50 years and above from the cohorts received three months interventions of Brahmi Ghrita (BG) (n=9), Brahmi extract (n=9), and Plain Ghee (n=8). MRS data were analyzed using analysis of covariance (ANCOVA) and Bonferroni post-hoc-tests for comparisons between age-groups, and paired-t-test was performed for pre- and post-intervention comparisons. Partial correlations were performed between neurometabolites and neuropsychological scores, controlling SNR, gender. Our results showed increased concentration of tCho, tCr, mI and tNAA in anterior and posterior cingulate cortex with aging. The increased concentration of these metabolites correlated positively with the age whereas metabolites tCho, tCr, and mI correlated inversely with auditory verbal learning (AVL), immediate recall, and delayed recall memory. The preliminary post-intervention findings revealed that the dietary fat-based formulation of Bacopa monnieri (BG) partially reversed the increase concentration of tCho, tCr, mI and improved AVL, digit span forward (DS-F) cognitive function performance. Overall, the results of the study suggest that BG can be potential prophylactic intervention for brain, especially in ageing population.</p>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":" ","pages":"106163"},"PeriodicalIF":4.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia Beyond Boundaries: Paradigm Shifts in Origin, Distribution, State Diversity, and Therapeutic Regeneration.","authors":"Zhida Lan, Hong Liu, Chao Huang, Jiali Li, Ziwei Dai, Yimin Yuan, Cheng He, Shangyao Qin, Zhida Su","doi":"10.1016/j.neuint.2026.106170","DOIUrl":"https://doi.org/10.1016/j.neuint.2026.106170","url":null,"abstract":"<p><p>Microglia have undergone a fundamental redefinition, transitioning from traditional CNS-restricted scavengers to a highly dynamic and systemically distributed immune lineage. This review synthesizes recent paradigm shifts that challenge long-standing concepts in neuroimmunology. We first discuss the revision of the classical vascular extravasation model by a newly identified integrin-dependent pial surface migration route for embryonic microglial progenitors. Second, we introduce the expanded concept of the \"microglial lineage,\" which includes transcriptionally and ontogenetically homologous cells residing not only in the CNS but also in peripheral tissues such as the skin, heart, and peripheral nervous system, suggesting broader physiological functions. Third, we highlight the transition from the obsolete M1/M2 polarization model to a microenvironment-driven, dynamic multimodal framework that captures the complex and context-dependent nature of microglial states in health and disease. Finally, we review breakthroughs in regenerative therapy, from pharmacologically induced repopulation to exogenous replacement using iPSC-derived or gene-corrected microglia, offering new hope for genetic microgliopathies such as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Collectively, these advances position microglia as central mediators of neuro-immune crosstalk and open novel avenues for treating neurodegenerative, neuroinflammatory, and developmental brain disorders.</p>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":" ","pages":"106170"},"PeriodicalIF":4.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JNK inhibition suppresses microglial NLRP3 activation and oxidative stress but unexpectedly worsens pain in diabetic neuropathy: insights from a combined in vitro and in vivo pharmacological study.","authors":"Li Ling, Tahir Ali, Xiang Li, Shuayan Gui, Haiyan Zhao, Xiaoying Zeng, Mingyue Lv, Caixue Duan","doi":"10.1016/j.neuint.2026.106167","DOIUrl":"https://doi.org/10.1016/j.neuint.2026.106167","url":null,"abstract":"<p><p>Diabetic neuropathy (DN) is driven by neuroinflammation and oxidative stress, with c-Jun N-terminal kinase (JNK) as a key mediator; however, the effects of JNK inhibition on neuropathic pain remain unclear. Therefore, we investigated the therapeutic potential of the JNK inhibitor SP600125 in a type 2 diabetic mouse model using combined in vitro and in vivo approaches. BV2 microglia were exposed to high glucose, lipopolysaccharide, palmitic acid, or hydrogen peroxide (H₂O₂) with or without SP600125 (10 nM). The PPARγ antagonist GW9662 was used for mechanistic dissection. Diabetic mice received SP600125 (15 mg/kg/day) or vehicle for 7 weeks. In vitro, SP600125 attenuated JNK phosphorylation and suppressed pro-inflammatory activation via NF-κB and NLRP3 in a PPARγ-dependent manner. SP600125 reduced palmitate-induced oxidative stress but exacerbated H₂O₂-induced injury (p < 0.0001), revealing context-dependent redox modulation. In vivo, SP600125 reduced diabetes-induced lipid accumulation and microglial reactivity while shifting microglia to an anti-inflammatory phenotype; however, it did not alter NLRP3, ASC, IKKα, or PPARγ expression. Despite these effects, SP600125 paradoxically worsened mechanical allodynia and thermal hyperalgesia. Together, these findings indicate that JNK inhibition provides anti-inflammatory and anti-lipid effects but paradoxically exacerbates pain, revealing a critical dissociation between neuroprotection and pain modulation in diabetic neuropathy.</p>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":" ","pages":"106167"},"PeriodicalIF":4.0,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupting PQBP1-eEF2 protein-protein interaction: From synaptic translation to immunity and cancer.","authors":"Emadeldin M Kamel, Sally Mostafa Khadrawy, Mohamed A M Ali, Noha A Ahmed, Nour Y S Yassin, Saleh Alkhedhairi, Faris F Aba Alkhayl, Al Mokhtar Lamsabhi","doi":"10.1016/j.neuint.2026.106154","DOIUrl":"https://doi.org/10.1016/j.neuint.2026.106154","url":null,"abstract":"<p><p>Polyglutamine-binding protein 1 (PQBP1) has emerged as a multifaceted regulator of gene expression, acting not only in the nucleus to influence transcription and splicing but also in the cytoplasm to control protein synthesis. A recent discovery identified a direct interaction between PQBP1 and the translation elongation factor eEF2, unveiling a new checkpoint in the elongation phase of protein synthesis. PQBP1 binds preferentially to the non-phosphorylated form of eEF2 and protects it from phosphorylation at Thr56 by its kinase eEF2K. Through this mechanism, PQBP1 promotes continuous elongation under conditions where unchecked eEF2K activity would otherwise stall ribosomes. The PQBP1-eEF2 complex plays critical roles in maintaining global proteome homeostasis and enabling activity-dependent protein synthesis in neurons. Disruption of this protein-protein interaction (PPI), whether by genetic mutations in PQBP1 or by sequestration of PQBP1 in cellular aggregates, has been linked to pathological states ranging from intellectual disability and impaired synaptic plasticity to altered innate immune responses and possibly tumorigenesis. In this review, we summarize the current understanding of the PQBP1-eEF2 interaction, its structural basis and regulation, the physiological processes it governs, and the consequences of its disruption in disease. We also discuss therapeutic considerations - when stabilizing this interaction might be beneficial (e.g. to restore synaptic function in neurodegeneration) versus when inhibiting it could be advantageous (e.g. to dampen excessive translation in cancer). Finally, we highlight experimental strategies and open questions for future research on this newly recognized nexus of translation control.</p>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"196 ","pages":"106154"},"PeriodicalIF":4.0,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinoic acid signaling regulates astrocyte reactivity by modulating MAPK/NF-κB pathways and mitochondrial integrity","authors":"Seo Hyun Yoo ,&nbsp;Dongyun Kim ,&nbsp;Gyu-Bum Yeon ,&nbsp;Jaeyeon Choi ,&nbsp;Jaewook Lee ,&nbsp;Dong-Wook Kim ,&nbsp;Hyunggee Kim ,&nbsp;Dae-Sung Kim","doi":"10.1016/j.neuint.2026.106134","DOIUrl":"10.1016/j.neuint.2026.106134","url":null,"abstract":"<div><div>Astrocytes respond to inflammatory stimuli by adopting a reactive state characterized by morphological, molecular, and functional changes that affect tissue repair and disease progression. A key feature of this transformation is the metabolic shift that supports inflammatory signaling and cytokine production. Retinoic acid (RA) modulates immune responses in the peripheral system; however, its role in astrocyte reactivity remains poorly understood. In this study, we investigated alterations in RA metabolism using an <em>in vitro</em> model of reactive astrocytes derived from human pluripotent stem cells. Reactivity was induced by treatment with tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), and complement component 1q (C1q), collectively referred to as TIC, and characterized using comprehensive morphological, molecular and functional analyses. We found that the induced reactive astrocytes exhibited a marked downregulation of key biosynthetic enzymes in RA metabolism, leading to a net decrease in intracellular RA levels. Exogenous RA supplementation attenuated TIC-induced expression of pro- and anti-inflammatory mediators, including IL-6, IL-8, nitric oxide, IL-10, and TGFβ. Mechanistically, RA suppressed these inflammatory responses by inhibiting NF-κB activation, likely through upstream attenuation of ERK and p38 MAPK pathways via upregulation of MAPK phosphatase 1 (MKP-1). In neuron and TIC-treated astrocyte co-cultures, RA treatment reduced the density of cleaved caspase 3-positive apoptotic-like neurons, an effect accompanied by decreased nitric oxide levels. These observations coincided with the restoration of mitochondrial integrity and mitophagy. Taken together, these findings identify RA metabolism as a key regulatory node in astrocyte reactivity and suggest a potential therapeutic role for RA in neuroinflammatory conditions.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"194 ","pages":"Article 106134"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147269413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcineurin inhibition mitigates activation of enteric glia in vitro and affects their crosstalk with macrophages","authors":"Aurora Patti ,&nbsp;Cristiana Lucia Rita Lipari ,&nbsp;Armando Genazzani ,&nbsp;Maria Angela Sortino ,&nbsp;Sara Merlo","doi":"10.1016/j.neuint.2026.106123","DOIUrl":"10.1016/j.neuint.2026.106123","url":null,"abstract":"<div><div>Multiple factors contribute to the physiopathology of inflammatory bowel diseases (IBD) and the enteric nervous system is emerging as a key player in this context. In particular, enteric glial cells (EGCs) share very similar properties with central astrocytes, play a homeostatic function under basal conditions, but can be activated by inflammatory stimuli further contributing to mucosal damage. Calcineurin (CN) is an important mediator of astrocyte inflammation and has been described also in EGCs. The aim of this study was to establish an <em>in vitro</em> model of EGCs challenged with an inflammatory insult to better delineate the role of CN in their inflammatory reaction and interaction with immune cells. EGCs stimulated with LPS + ATP (5 μg/mL-2 mM) for 24 h showed typical inflammatory features with increased expression of the astrocyte marker GFAP, the inflammasome component NLRP3 and the alarmin HMGB1. Inhibition of CN by cyclosporin A (CsA, 1 μM) counteracted these effects and increased the expression of nuclear HMGB1. Nuclear translocation of NF-κB p65 induced by LPS + ATP was also blunted by CsA pre-treatment. The migration of RAW 264.7 macrophages co-cultured with LPS + ATP-stimulated EGCs was enhanced, an effect prevented by CsA. This was accompanied by activation of macrophages to a pro-inflammatory phenotype, as shown by increased COX-2, IL-1β and TNF-α gene expression. Inhibition of CN in EGCs reduced this response while increasing the phagocytic capacity of macrophages. Altogether the results here reported identify a central role for CN in the inflammatory response of EGCs and their crosstalk with cells of the immune system, supporting potential new sites of intervention for drugs targeting CN.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"194 ","pages":"Article 106123"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of 5-HT1A receptors in the ventrolateral orbital cortex alleviates neuropathic pain-induced depressive-like behaviors via GABAergic neurons in male rats","authors":"Yu-long Zhao ,&nbsp;Hui-yuan Yi ,&nbsp;Xue-mei Hou ,&nbsp;Xiao-chen La ,&nbsp;Sani Sa'idu Baba ,&nbsp;Yi-xiao Guo ,&nbsp;Rong-rong Yao ,&nbsp;Xiao-cui Yuan ,&nbsp;Qi-rui Zhang ,&nbsp;Hong Jia ,&nbsp;Yu-ying Wang ,&nbsp;Fu-quan Huo","doi":"10.1016/j.neuint.2026.106133","DOIUrl":"10.1016/j.neuint.2026.106133","url":null,"abstract":"<div><div>Neuropathic pain is frequently comorbid with depression, which exacerbates patient suffering and complicates clinical management. Although the ventrolateral orbital cortex (VLO) is involved in pain processing and emotional regulation, its specific role in neuropathic pain-induced depression remains unclear. Emerging evidence implicates 5-HT_1A receptors in modulating both pain and mood disorders via GABAergic transmission, yet their specific contributions in the VLO are not fully understood. Here, we aimed to investigate whether and how VLO 5-HT_1A receptors mediate depressive-like behaviors associated with neuropathic pain in male rats. Using a spared nerve injury (SNI) model, combined with neuropharmacological, chemogenetic, and cell-type-specific adeno-associated virus (AAV) approaches, we found that activating VLO 5-HT_1A receptor produced dose-dependent antidepressant effects, which were blocked by a selective antagonist. Mechanistically, 5-HT_1A receptor-mediated antidepressant effects were enhanced by a GABA_A receptor antagonist and suppressed by a GABA_A receptor agonist. Chemogenetic activation of VLO GABAergic neurons abolished the antidepressant effects of 5-HT_1A receptor stimulation. Furthermore, SNI-induced depressive-like behaviors correlated with reduced 5-HT_1A receptor expression in the VLO. AAV-mediated 5-HT_1A receptor overexpression specifically on GABAergic neurons alleviated depressive-like behaviors in SNI rats, while knockdown induced depressive-like phenotypes in wild-type rats. In conclusion, our findings demonstrate that 5-HT_1A receptors in the VLO alleviate neuropathic pain-induced depressive-like behaviors through a GABAergic disinhibition mechanism. This study highlights 5-HT_1A receptors in the VLO as promising therapeutic targets for mood disturbances associated with neuropathic pain, offering a cortical framework for comorbid pain-depression pathophysiology.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"194 ","pages":"Article 106133"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146256939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APOE4 induces sex-dependent synaptic mitochondrial cholesterol, proteome, and respiratory function alterations in mice","authors":"Nashanthea J. Roland,&nbsp;Johnny W. Zigmond,&nbsp;Jane E. Manganaro,&nbsp;L. Daniel Estrella,&nbsp;Kelly L. Stauch","doi":"10.1016/j.neuint.2026.106125","DOIUrl":"10.1016/j.neuint.2026.106125","url":null,"abstract":"<div><div>Alzheimer's disease (AD), the leading cause of dementia, is characterized by synapse damage and loss, correlating strongly with cognitive decline. APOE4, the strongest genetic risk factor for AD, impairs synapses with the mechanisms remaining unclear. APOE, the central nervous system's primary lipid and cholesterol carrier, is critical for axonal growth, synapse formation, and spine remodeling. To investigate how APOE4 affects cholesterol and synaptic dysfunction, we studied male and female human APOE3 and APOE4 knock-in mice. Cholesterol levels were measured in brain homogenates, synaptosomes, and mitochondria using bioluminescent assays, and APOE protein expression was analyzed via immunoblotting. Proteomics of synaptosomes and mitochondrial respiratory function assessments were performed using mass spectrometry and the Seahorse XF Analyzer, respectively. We found that cholesterol levels did not differ between APOE3 and APOE4 mice in brain homogenates or synaptosomes. However, male APOE4 mice exhibited lower cholesterol levels in synaptic mitochondria than APOE3 mice, with no changes in non-synaptic mitochondria or female mice. APOE protein was present in synaptosomes and mitochondrial fractions without changes due to APOE4 expression. Synaptosomal proteomics uncovered synaptic mitochondrial membrane proteins were differentially expressed in APOE4 versus APOE3 mice. Proteomic analysis also revealed altered neurotransmitter signaling and metabolic pathways in the APOE4 mice, predominantly in males. Notably, proteins involved in synaptic vesicle endocytosis and aerobic respiration were differentially expressed. Mitochondrial respiratory function was disrupted in female APOE4 mice, which displayed increased maximal respiration and spare respiratory capacity at the synapse. These findings identify a role for APOE in regulating synaptic mitochondrial cholesterol, protein expression, and respiratory function in a sex-dependent manner, contributing to synaptic dysfunction in AD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"194 ","pages":"Article 106125"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146199761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitamin B1 protects against Aβ1-42-induced HIF-1α activation and neurotoxicity","authors":"Yasmin Tarek Anderson,&nbsp;Katherine Priest,&nbsp;Jason Zastre","doi":"10.1016/j.neuint.2026.106130","DOIUrl":"10.1016/j.neuint.2026.106130","url":null,"abstract":"<div><div>Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and extensive neuronal loss, largely driven by amyloid beta (Aβ) accumulation and associated cellular stress. Vitamin B1 (thiamine) supplementation has demonstrated cognitive benefits in clinical AD studies, however, the mechanisms underlying thiamine's neuroprotective effects remain unclear. Here, we investigated whether thiamine mitigates Aβ_1-42-induced neurotoxicity by suppressing hypoxia-inducible factor-1 alpha (HIF-1α), a transcriptional stress factor regulating many proapoptotic and progressive amyloidogenic pathways. Exposure of neuronal cells to Aβ_1-42 oligomers increased reactive oxygen species (ROS) accumulation, decreased intracellular Fe²⁺, and induced HIF-1α stabilization. HIF-1α activation by Aβ_1-42 promoted apoptosis through increased endoplasmic reticulum (ER) stress and increased mitochondrial dimerization of BNIP3. Thiamine supplementation significantly reduced cellular ROS levels, preserved intracellular Fe²⁺ levels, and restored prolyl hydroxylase (PHD) activity to promote HIF-1α hydroxylation and degradation. Suppression of HIF-1α by thiamine attenuated ER and BNIP3-driven apoptotic pathways and preserved neuronal viability. Thiamine further mitigated HIF-1α-mediated amyloidogenic progression, limiting feedback toxicity caused by Aβ_1-42. These results demonstrate that thiamine protects against Aβ_1-42-mediated neurotoxicity by reducing ROS, preserving Fe²⁺, and inhibiting HIF-1α-driven pathological cascades. Overall, this study identified a novel mechanism for thiamine's neuroprotective role, further supporting its therapeutic potential to limit neurodegenerative progression in AD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"194 ","pages":"Article 106130"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218153","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}