Translational Psychiatry最新文献

The sense and nonsense of antipsychotic combinations: A model for dopamine D_2/3 receptor occupancy. 抗精神病药物组合的意义与无意义：多巴胺D2/3受体占用模型。

IF 6.2 1区医学

Translational Psychiatry Pub Date : 2025-10-01 DOI: 10.1038/s41398-025-03582-2

Moritz Spangemacher, Christian N Schmitz, Paul Cumming, Luca V Färber, Xenia M Hart, Hiroyuki Uchida, Gerhard Gründer

{"title":"The sense and nonsense of antipsychotic combinations: A model for dopamine D2/3 receptor occupancy.","authors":"Moritz Spangemacher, Christian N Schmitz, Paul Cumming, Luca V Färber, Xenia M Hart, Hiroyuki Uchida, Gerhard Gründer","doi":"10.1038/s41398-025-03582-2","DOIUrl":"10.1038/s41398-025-03582-2","url":null,"abstract":"Approximately 20-30% of patients treated for schizophrenia concomitantly take two or more antipsychotic substances, despite the limited evidence that antipsychotic combination treatment is superior to monotherapy. Positron emission tomography (PET) studies can reveal the relationship between plasma levels of an antipsychotic medication and occupancy at striatal dopamine D2/3 receptors (D2R), but there is scant consideration in the literature of the net occupancy obtained with antipsychotic combination treatment. In this report, we introduce a novel model for predicting net D2R occupancy in antipsychotic polypharmacy (APP); taking as illustrative examples five commonly prescribed antipsychotic medications. In an extension of the law of mass action for predicting receptor occupancy from the plasma concentration of a single psychopharmacological agent, we test a model for inferring the net striatal D2R occupancy in APP from the individual Michaelis-Menten kinetics of two (or more) antipsychotic medications. Based on literature PET findings for striatal D2R occupancy in monotherapy, our model predicts that widely used antipsychotic medication combinations may exceed the optimal therapeutic window of 65-80% occupancy. Our extended model accurately predicted occupancy for the only APP combination documented by PET. Present results call for caution in the design of antipsychotic medication combination therapy, aiming to avoid excessive occupancy by adjusting drug concentrations and doses.","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"348"},"PeriodicalIF":6.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12488982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: Potential causal association between gut microbiome and posttraumatic stress disorder. 更正：肠道微生物组与创伤后应激障碍之间存在潜在的因果关系。

IF 6.2 1区医学

Translational Psychiatry Pub Date : 2025-09-30 DOI: 10.1038/s41398-025-03628-5

Qiang He, Wenjing Wang, Dingkang Xu, Yang Xiong, Chuanyuan Tao, Chao You, Lu Ma, Junpeng Ma

引用次数: 0

Deep brain stimulation of medial forebrain bundle modulates noradrenergic activity and feedforward inhibition in rodent model of depression. 深部脑刺激内前脑束调节抑郁症啮齿动物去甲肾上腺素能活性和前馈抑制。

IF 6.2 1区医学

Translational Psychiatry Pub Date : 2025-09-29 DOI: 10.1038/s41398-025-03577-z

Zhuo Duan, Yixin Tong, Volker A Coenen, Máté D Döbrössy

{"title":"Deep brain stimulation of medial forebrain bundle modulates noradrenergic activity and feedforward inhibition in rodent model of depression.","authors":"Zhuo Duan, Yixin Tong, Volker A Coenen, Máté D Döbrössy","doi":"10.1038/s41398-025-03577-z","DOIUrl":"10.1038/s41398-025-03577-z","url":null,"abstract":"Deep Brain Stimulation (DBS) of the superolateral medial forebrain bundle has shown promising long-term anti-depressant effects in treatment-resistant depression patients, although the mechanisms are not clear. The study explored medial forebrain bundle DBS mediated modulation of central noradrenaline transmission in a rodent depression model, the Flinders Sensitive Line (FSL), and in controls, Sprague Dawley (SD) rats. In vivo noradrenergic signaling in the prefrontal cortex (PFC) and nucleus accumbens (NAc) and ultrasonic vocalization were monitored during unilateral mfb-DBS across diverse stimulation parameters. The fiber amount, myelination status, and the activation of ascending projected noradrenergic cell groups (A1, A2, A6) were quantified. Moreover, stimulation induced changes in the parvalbumin-mediated feedforward microcircuitry and neuron activation at PFC and NAc were assessed. FSL rats showed decrease in NA fibers in mfb. Stimulation increased PFC noradrenergic signaling similarly across both groups compared to baseline, but in the NAc, the FSLs had notably higher signaling compared with SDs. FSLs demonstrated more positive affective ultrasonic vocalizations post-DBS than SDs. Brainstem nuclei A1 and A2 had similar noradrenergic neuron density across the experimental groups, and mfb DBS increased neuronal activation in both groups. FSLs had fewer noradrenergic neurons in the A6 nuclei, fewer unmyelinated noradrenergic fibers traversing the mfb, and decreased parvalbumin interneuron activity in both PFC and NAc. DBS normalized parvalbumin interneuron activity in the FSL rats. The study proposes that mfb DBS, via the modulation of the central NA system and the GABAergic inhibitory control of neural excitability, likely contributes to the anti-depressant therapeutic mechanisms reported in both clinical and experimental studies.","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"343"},"PeriodicalIF":6.2,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12480665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neurometabolic predictors of mental effort in the frontal cortex. 额叶皮层脑力活动的神经代谢预测因子。

IF 6.2 1区医学

Translational Psychiatry Pub Date : 2025-09-29 DOI: 10.1038/s41398-025-03554-6

Arthur Barakat, Jules Brochard, Mathias Pessiglione, Jean-Philippe Godin, Bernard Cuenoud, Lijing Xin, Nicolas Clairis, Carmen Sandi

{"title":"Neurometabolic predictors of mental effort in the frontal cortex.","authors":"Arthur Barakat, Jules Brochard, Mathias Pessiglione, Jean-Philippe Godin, Bernard Cuenoud, Lijing Xin, Nicolas Clairis, Carmen Sandi","doi":"10.1038/s41398-025-03554-6","DOIUrl":"10.1038/s41398-025-03554-6","url":null,"abstract":"Motivation drives individuals to overcome costs to achieve desired outcomes, such as rewards or avoidance of punishment, with significant variability across individuals. The dorsomedial prefrontal cortex/dorsal anterior cingulate cortex (dmPFC/dACC) and anterior insula are key brain regions implicated in effort-based decision-making. Here, we utilized proton magnetic resonance spectroscopy (1H-MRS) at 7 Tesla on 69 healthy participants in these brain regions to uncover the neurometabolic factors that influence these differences. We designed and applied an effort-based decision-making task requiring mental and physical effort to probe motivated behavior, complemented by computational modeling to extract key behavioral parameters. Gradient boosting machine learning was applied to explore the predictive role of specific metabolites in motivated behavior. Our results reveal that a model established on dmPFC/dACC metabolites explains decisions to exert high mental effort and sensitivity to mental effort. In particular, glutamate, aspartate, and lactate in dmPFC/dACC, three metabolites linked through the tricarboxylic acid cycle and glycolysis, were identified as key discriminative metabolites in the dmPFC/dACC, predictive of mental effort choices, underpinning energy supply and cognitive processes. Anterior insula metabolites did not significantly relate to effort-related decisions. Notably, glutamine and lactate levels between the periphery (plasma) and the dmPFC/dACC were correlated, suggesting a metabolic link between peripheral and central biomarkers of effort. Our findings provide novel insights into the neurometabolic underpinnings of motivated behavior and propose novel biomarkers for mental effort-based decision-making. Importantly, our study highlights the relevance of multivariable approaches in elucidating complex cognitive functions.","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"344"},"PeriodicalIF":6.2,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Meta-analysis of the brain transcriptomes of multiple genetic mouse models of schizophrenia highlights dysregulation in striatum and thalamus. 对多种精神分裂症遗传小鼠模型的脑转录组的荟萃分析显示纹状体和丘脑的失调。

IF 6.2 1区医学

Translational Psychiatry Pub Date : 2025-09-29 DOI: 10.1038/s41398-025-03563-5

Kira A Perzel Mandell, Sean K Simmons, Ajay Nadig, Zohreh Farsi, Wei-Chao Huang, Sameer Aryal, Min Jee Kwon, Bryan Song, Kira Brenner, Nate Shepard, Ally A Nicolella, Lesley D O'Brien, Aron H Lichtman, Joshua Z Levin, Morgan Sheng

{"title":"Meta-analysis of the brain transcriptomes of multiple genetic mouse models of schizophrenia highlights dysregulation in striatum and thalamus.","authors":"Kira A Perzel Mandell, Sean K Simmons, Ajay Nadig, Zohreh Farsi, Wei-Chao Huang, Sameer Aryal, Min Jee Kwon, Bryan Song, Kira Brenner, Nate Shepard, Ally A Nicolella, Lesley D O'Brien, Aron H Lichtman, Joshua Z Levin, Morgan Sheng","doi":"10.1038/s41398-025-03563-5","DOIUrl":"10.1038/s41398-025-03563-5","url":null,"abstract":"Schizophrenia is a severe mental illness with high heritability, but its underlying mechanisms are poorly understood. We meta-analyzed large-scale brain transcriptomic data from mice harboring individual loss-of-function mutations in seven schizophrenia risk genes (Akap11, Dagla, Gria3, Grin2a, Sp4, Srrm2, Zmym2). While all studied brain regions were affected, the striatum and the thalamus emerged as key brain regions of convergence. Striatum showed downregulation of synapse- and oxidative phosphorylation-related gene sets in all models. In the thalamus, mutants separated into two groups based on transcriptomic phenotype: synapse-related gene sets were upregulated in mutants with only schizophrenia and bipolar association, and were downregulated in mutants that are associated with developmental delay/intellectual disability in addition to schizophrenia. Overall, our meta-analysis reveals convergence and divergence in brain transcriptomic phenotype in these schizophrenia genetic models, supports the involvement of striatal disturbance and synapse dysfunction in schizophrenia, and points to a key role of the thalamus.","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"345"},"PeriodicalIF":6.2,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12480767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The burden of mental disorders, substance use disorders, and self-harm among youths globally: findings from the 2021 Global Burden of Disease study. 全球青少年精神障碍、物质使用障碍和自残负担：来自2021年全球疾病负担研究的结果

IF 6.2 1区医学

Translational Psychiatry Pub Date : 2025-09-29 DOI: 10.1038/s41398-025-03533-x

Jin-Jie Xu, Lu-Yu Ding, Cong-Cong Sun, Yu Qiao, Mei-Ti Wang, Jin-Xin Zheng, Gang Wang

{"title":"The burden of mental disorders, substance use disorders, and self-harm among youths globally: findings from the 2021 Global Burden of Disease study.","authors":"Jin-Jie Xu, Lu-Yu Ding, Cong-Cong Sun, Yu Qiao, Mei-Ti Wang, Jin-Xin Zheng, Gang Wang","doi":"10.1038/s41398-025-03533-x","DOIUrl":"10.1038/s41398-025-03533-x","url":null,"abstract":"The period from childhood to early adulthood is critically susceptible to the onset of mental disorders (MDs), substance use disorders (SUDs), and self-harm, with significant implications for public health policy. Understanding these trends over time and across different regions is essential for effective intervention and resource allocation. This study utilizes data from GBD 2021, focusing on youths aged 10-24 years globally. Data span from 1990 to 2021, providing a longitudinal perspective on trends and are stratified by age groups, gender, geographic regions, and Socio-demographic Index (SDI). The results showed that in 2021, the global standardized prevalence of MDs among youths reached 14,778 per 100,000, marking a 6.8%(4.7-9.0) increase from 1990. Anxiety disorders and depressive disorders exhibited the highest prevalence. The prevalence of SUDs decreased by 20.3%(17.4-22.9) since 1990, while self-harm rates decreased by 35%(33.6-38.3). The highest burden was observed in the 20-24 age group, with notable gender disparities: females had higher rates of anxiety and depressive disorders, whereas males were more affected by SUDs and conduct disorders. Geographical and socio-economic variations were pronounced, with high SDI regions exhibiting the most significant prevalence of most MDs and SUDs. The study highlights a significant rise in the burden of MDs among global youth over three decades, exacerbated during the COVID-19 pandemic. It underscores the need for targeted mental health interventions and resource allocation to address the escalating mental health needs of young populations.","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"346"},"PeriodicalIF":6.2,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CD38 connects the heart and brain. CD38连接心脏和大脑。

IF 6.2 1区医学

Translational Psychiatry Pub Date : 2025-09-11 DOI: 10.1038/s41398-025-03597-9

Yijing Tao, Jiahao Duan, Kai Huang, Ruting Wang, Qinwen Feng, Chun Yang, Xinying Zhang, Ling Yang

引用次数: 0

A pilot study examining a ketogenic diet as an adjunct therapy in college students with major depressive disorder. 一项试点研究，检查生酮饮食作为大学生抑郁症的辅助治疗。

IF 6.2 1区医学

Translational Psychiatry Pub Date : 2025-09-10 DOI: 10.1038/s41398-025-03544-8

Drew D Decker, Ryan Patel, Jennifer Cheavens, Scott M Hayes, Whitney Whitted, Ann J Lee, Alex Buga, Bradley T Robinson, Christopher D Crabtree, Madison L Kackley, Justen T Stoner, Teryn N Sapper, Ashwini Chebbi, Jeff S Volek

{"title":"A pilot study examining a ketogenic diet as an adjunct therapy in college students with major depressive disorder.","authors":"Drew D Decker, Ryan Patel, Jennifer Cheavens, Scott M Hayes, Whitney Whitted, Ann J Lee, Alex Buga, Bradley T Robinson, Christopher D Crabtree, Madison L Kackley, Justen T Stoner, Teryn N Sapper, Ashwini Chebbi, Jeff S Volek","doi":"10.1038/s41398-025-03544-8","DOIUrl":"10.1038/s41398-025-03544-8","url":null,"abstract":"A ketogenic diet (KD) has shown promise as an adjunctive therapy for neurological and neuropsychiatric disorders, including bipolar disorder and major depressive disorder (MDD). We examined tolerance for a KD in young adults with MDD and assessed symptoms of depression and metabolic health. Students (n = 24) with a confirmed diagnosis of MDD at baseline receiving standard of care counseling and/or medication treatment were enrolled in a 10-12 week KD intervention that included partial provision of ketogenic-appropriate food items, frequent dietary counseling, and daily morning tracking of capillary R-beta-hydroxybutyrate (R-BHB). Primary outcome measures for mood symptoms included the Patient Health Questionnaire (PHQ-9) and Hamilton Rating Scale for Depression (HRSD). Additional outcomes included body composition, neurocognitive function, and blood hormonal and inflammatory markers. Sixteen students (10 women, 6 men, mean age 24 yr) completed the intervention. Nutritional ketosis (R-BHB > 0.5 mM) was achieved 73% of the time. Depressive symptoms decreased by 69% (PHQ-9) and 71% (HRSD) post-intervention (p < 0.001), with improvement occurring within 2-6 weeks. Global well-being increased nearly 3-fold (p < 0.001). Participants lost body mass (-6.2%; p = 0.002) and fat mass (-13.0%; p < 0.001). Serum leptin decreased (-52%; p = 0.009) and brain-derived neurotropic factor increased (+32%; p = 0.029). Performance improved on several cognitive tasks. In students with mild to moderate depression based on PHQ-9 and HRSD, implementation of a WFKD for 10-12 weeks is a feasible adjunctive therapy and may be associated with improvements in depression symptoms, well-being, body composition, and cognition.","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"322"},"PeriodicalIF":6.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12420795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145030627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Blunted anterior midcingulate response to reward in opioid users is normalized by prefrontal transcranial magnetic stimulation. 经颅前额叶磁刺激可使阿片类药物使用者对奖励的前扣带反应钝化。

IF 6.2 1区医学

Translational Psychiatry Pub Date : 2025-09-03 DOI: 10.1038/s41398-025-03569-z

Kathryn Biernacki, Rita Z Goldstein, Malte R Güth, Nelly Alia-Klein, Sally Cole, Suchismita Ray, Travis E Baker

{"title":"Blunted anterior midcingulate response to reward in opioid users is normalized by prefrontal transcranial magnetic stimulation.","authors":"Kathryn Biernacki, Rita Z Goldstein, Malte R Güth, Nelly Alia-Klein, Sally Cole, Suchismita Ray, Travis E Baker","doi":"10.1038/s41398-025-03569-z","DOIUrl":"10.1038/s41398-025-03569-z","url":null,"abstract":"Abnormalities in goal-directed behavior, mediated by mesocorticolimbic reward system, contribute to worse clinical outcomes including higher risk of treatment dropout and drug relapse in opioid users (OU). Despite efforts to counteract such neural alterations, brain-based interventions for this disorder remain ineffective. In this sham-controlled randomized study, we report the initial results on the efficacy of transcranial magnetic stimulus (TMS) in normalizing reward functioning in this population. During a reward-based choice task, we applied robot-assisted 10-Hz TMS to the prefrontal cortex in OU (Active = 16, Sham = 18) and matched healthy controls (HC, Active = 22, Sham = 24) while we recorded the reward positivity - an electrophysiological signal believed to index sensitivity of the anterior midcingulate cortex (MCC) to rewards. A robotic arm positioned a TMS coil over a prefrontal cortex target, and 50 pulses were delivered at 10-Hz before every 10 trials (2000 pulses, 400 trials). Our results revealed an interaction between TMS (Active vs Sham) and Group (OU vs HC) (F1,72 = 6.9, p = 0.01, η2 = 0.09). First, in the Sham TMS condition, OU exhibited a blunted reward positivity compared to HC (p = 0.01, d = 0.84). Second, OU receiving active TMS displayed a larger reward positivity compared to OU receiving sham (p = 0. 003, d = 0.98), and no differences were observed between OU and HC (p = 0.42, d = 0.17) or HC receiving sham (p = 0.48, d = 0.11). We envision that targeting a specific frontal-cingulate reward pathway is an important first step to maintain long-terms effect of TMS on MCC reward function, which may enhance treatment success through the maintenance of treatment goals.","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"340"},"PeriodicalIF":6.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12408835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nesfatin-1 ameliorates blood-brain barrier dysfunction in Alzheimer's disease by targeting VEGF-R1 and reducing cellular senescence in brain vascular endothelial cells. Nesfatin-1通过靶向VEGF-R1和减少脑血管内皮细胞衰老，改善阿尔茨海默病的血脑屏障功能障碍。

IF 6.2 1区医学

Translational Psychiatry Pub Date : 2025-09-03 DOI: 10.1038/s41398-025-03528-8

Biyue Zhang, Shumei Zhang, Zeming Guo, Chunzhan Hong, Futian Zhang, Huasong Lin

{"title":"Nesfatin-1 ameliorates blood-brain barrier dysfunction in Alzheimer's disease by targeting VEGF-R1 and reducing cellular senescence in brain vascular endothelial cells.","authors":"Biyue Zhang, Shumei Zhang, Zeming Guo, Chunzhan Hong, Futian Zhang, Huasong Lin","doi":"10.1038/s41398-025-03528-8","DOIUrl":"10.1038/s41398-025-03528-8","url":null,"abstract":"Cellular senescence and associated endothelial permeability are crucial factors in the dysfunction of the blood-brain barrier (BBB) in neurodegenerative diseases, including Alzheimer's disease (AD). Nesfatin-1 (NF-1), a neuropeptide involved in regulating appetite and energy homeostasis, has not been extensively studied for its pathophysiological role in AD. In this study, we found that NF-1 treatment improved cellular senescence in brain vascular endothelial bEnd.3 cells by restoring the expression of hTERT and TERF2 against oligomerized Aβ1-42. Additionally, NF-1 reduced p53 and p21 protein levels in bEnd.3 cells exposed to oligomerized Aβ1-42. Notably, NF-1 reduced oligomerized Aβ1-42-induced endothelial monolayer permeability by maintaining transendothelial electric resistance (TEER) and the levels of tight junction proteins claudin 5 and ZO-1. Furthermore, NF-1 suppressed the expression of VEGF-R1 but not VEGF-R2 in bEnd.3 cells exposed to oligomerized Aβ1-42. Overexpression of VEGF-R1 negated the protective effects of NF-1 against oligomerized Aβ1-42-induced cellular senescence and increased endothelial monolayer permeability, indicating the involvement of VEGF-R1 in this process. Using a transgenic (Tg APPswe/PSEN1dE9) AD mouse model, we demonstrated that NF-1 administration lowered VEGF-R1 expression in the brain cortex of AD mice. Moreover, NF-1 mitigated BBB dysfunction and enhanced the expression of claudin 5 and ZO-1 in the brains of AD mice. Our results suggest that NF-1 may be a potential therapeutic strategy for treating AD.","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"341"},"PeriodicalIF":6.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12408809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0