Molecular Neurobiology最新文献

{"title":"Epigenetic Insights into Vascular Cognitive Impairment: DNA Methylation in the Human Brain Tissue.","authors":"Sangeetha Vishweswaraiah, Nazia Saiyed, Abdullah Khalid, Milda Milčiūtė, Migle Gabrielaite, Ceyda Buyuker, Boran Aksakal, Lorena Gomes, Juozas Gordevicius, Ali Yilmaz, Stewart F Graham","doi":"10.1007/s12035-025-05119-6","DOIUrl":"10.1007/s12035-025-05119-6","url":null,"abstract":"<p><p>Vascular cognitive impairment (VCI) is a common form of dementia that results from vascular damage to the brain, yet the underlying molecular mechanisms remain poorly understood. Epigenetic modifications, particularly DNA methylation, have been implicated in various neurodegenerative diseases, including VCI; however, the details of this association are lacking. This study analyzed Brodmann area 7 tissue samples from 19 individuals with VCI and 21 control subjects. DNA methylation profiles were analyzed using the Illumina EPIC array V2. Integrative bioinformatics approaches, including differentially methylated CpGs (DMCs), differentially methylated regions (DMRs), and gene set enrichment analysis (GSEA), were employed to identify dysregulated pathways associated with VCI. A sex-specific analysis was performed to explore potential differences in methylation patterns between males and females. The analysis revealed significant differential methylation across 3601 CpG sites, with a predominant pattern of hypermethylation (82%) observed in the VCI group. Notably, hypermethylation was detected in key genes related to neurodegeneration and vascular health, such as MTCH2, DPRX, and DENND4A. GSEA identified critical pathways related to neuronal function and vascular health. In sex-specific pathway analysis, vascular regulatory mechanisms were enriched in males and synaptic plasticity together with neuronal development in females. DMRs linked to RAB12 highlighted the role of lysosomal dysfunction in both cognitive and vascular deterioration. Our findings provide novel insights into the epigenetic landscape of VCI, revealing hypermethylation of genes involved in both neuronal and vascular health. The identification of sex-specific differences in epigenetic patterns underscores the need for tailored therapeutic strategies. These results offer potential biomarkers for early diagnosis and new avenues for therapeutic intervention targeting both vascular and neuronal components of VCI.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"13650-13664"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Effects of Niosome Curcumin on the Alteration of NF-κB Gene Expression and Memory and Learning in the Prefrontal Cortex of Alzheimer's Rats.","authors":"Elahe Asani, Homeira Hatami, Gholamreza Hamidian, Somayeh Hatami","doi":"10.1007/s12035-025-05148-1","DOIUrl":"10.1007/s12035-025-05148-1","url":null,"abstract":"<p><p>Alzheimer's disease is a neurodegenerative disorder that is the primary cause of dementia, affecting memory and learning abilities. Inflammation, oxidative stress, and the accumulation of heavy metals such as aluminum in the brain are hypothesized as key contributors to this disease. The aim of this study is to investigate the stereological changes and alterations in nuclear factor-kappa B (NF-κB) gene expression in the prefrontal cortex (PFC) of Alzheimer's male rats and the therapeutic effects of curcumin nanoparticles. Fifty-six adult male Wistar rats were divided into one of seven groups (n = 8): control, sham (ethanol), Alzheimer's disease (AD, AlCl3 at a dose of 4.2 mg/kg for 28 days), curcumin (Cur, 20 mg/kg), niosome curcumin (Niosome.Cur, 20 mg), AD + curcumin, and AD + niosome curcumin. Administration of free curcumin and niosome curcumin was carried out intraperitoneally for 14 and 7 days following the induction of Alzheimer's disease (AD). The object recognition test was performed to assess memory and learning parameters, and the T-maze test was conducted to evaluate working memory. Expression of the NF-κB inflammatory gene was detected using real-time PCR. Stereological evaluation was performed to quantitatively assess tissue damage. Results indicated that AD induction caused an increase in NF-κB gene expression, and both curcumin and niosome curcumin modulated this expression. Stereological changes revealed a quantitative increase in tissue damage in AD, and curcumin, particularly niosome curcumin, improved the disease state by modulating these parameters. Niosome curcumin enhanced memory in Alzheimer's disease. Finally, niosomes as drug-carrying nanoparticles offer a suitable option for better efficacy in a shorter time frame for antioxidants like curcumin.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"13707-13721"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Tasimelteon Treatment on Traumatic Brain Injury Through NRF-2/HO-1 and RIPK1/RIPK3/MLKL Pathways in Rats.","authors":"Eyyüp Sabri Özden, Mustafa Soner Özcan, Mehtap Savran, Ilter Ilhan, Muhammet Yusuf Tepebası, Mehmet Abdulkadir Sevuk, Özlem Özmen","doi":"10.1007/s12035-025-04711-0","DOIUrl":"10.1007/s12035-025-04711-0","url":null,"abstract":"<p><p>Secondary brain damageafter traumatic brain injury (TBI) involves oxidative stress, neuroinflammation, apoptosis, and necroptosis and can be reversed by understanding these molecular pathways. The objective of this study was to examine the impact of tasimelteon (Tasi) administration on brain injury through the nuclear factor erythroid 2-related factor 2 (NRF-2)/heme oxygenase-1 (HO-1) and receptor-interacting protein kinase 1 (RIPK1)/receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like (MLKL) pathways in rats with TBI. Thirty-two male Wistar albino rats weighing 300-350 g were randomly divided into four groups: the control group, trauma group, Tasi-1 group (trauma + 1 mg/kg Tasi intraperitoneally), and Tasi-10 group (trauma + 10 mg/kg Tasi intraperitoneally). At the end of the experimental phase, after sacrifice, blood samples and brain tissue were collected for biochemical, histopathological, immunohistochemical, and genetic analyses. Tasi increased the total antioxidant status and decreased the total oxidant status and oxidative stress index. In addition, Tasi caused histopathological changes characterized by a markedly reduced hemorrhage area in the Tasi-1 group. Normal brain and meningeal structure was observed in rats in the Tasi-10 group. Immunohistochemical analysis indicated that Tasi also decreased the expression of interferon-gamma, caspase-3, and tumor necrosis factor-alpha in the brain tissue. Although NRF-2 and HO-1 expression decreased, RIPK1/RIPK3/MLKL gene expression increased due to trauma. However, Tasi treatment reversed all these findings. Tasi protected against brain injury through the NRF-2/HO-1 and RIPK1/RIPK3/MLKL pathways in rats with TBI.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"12383-12392"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12433330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging Alzheimer's Disease Omics to Identify Pleiotropic Genes Contributing to Neurodegeneration in Primary Open-Angle Glaucoma.","authors":"Paulina Tolosa-Tort, Andrew T DeWan","doi":"10.1007/s12035-025-05074-2","DOIUrl":"10.1007/s12035-025-05074-2","url":null,"abstract":"<p><p>Primary open-angle glaucoma is the most common form of glaucoma worldwide and one of the leading causes of irreversible blindness. Current therapies focus on intraocular pressure control despite substantial evidence on the importance of additional pathogenic mechanisms involved in neuronal repair and regeneration. Some of these mechanisms may be shared with and across other neurodegenerative disorders, such as Alzheimer's disease. Joint analyses that address this pathogenic overlap can be leveraged to identify suspected neurodegenerative and neuroprotective pathways. In this study, we derived gene-level summary statistics from available genome-wide association studies for primary open-angle glaucoma and Alzheimer's Disease and employed a multivariate analysis to identify genes with an effect on both neurodegenerative diseases. We assessed the influence of the prioritized genes using Mendelian randomization to obtain the effect of retina- and brain cortex-specific gene expression on primary open-angle glaucoma risk. We identified ten genes with evidence of a pleiotropic effect on primary open-angle glaucoma and Alzheimer's disease: TMCO1, ANXA11, ARHGAP27, PLEKHM1, CRHR1, KANSL1, LRRC37A, ARL17A, LRRC37A2, and CBY1. Additionally, gene expression in either the retina or brain cortex of TMCO1, ANXA11, ARHGAP27, PLEKHM1, KANSL1, LRRC37A, ARL17A, LRRC37A2, and CBY1 influenced POAG risk. These genes have known roles in neurodegeneration-associated pathways. Our analysis uncovered evidence of pleiotropy and gene expression as a mechanism impacting disease risk. Further investigation into these genes may yield valuable insights into their involvement in neurodegenerative pathways potentially informing new approaches for early detection, classification, and treatment strategies.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"12488-12497"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of NLRP3 Inflammasome-associated Biomarkers by Integrated Bioinformatics Analysis in Neuropathic Pain.","authors":"Dongdong Liu, Shaopeng Huang, Yue Yuan, Jinfeng Liu","doi":"10.1007/s12035-025-04999-y","DOIUrl":"10.1007/s12035-025-04999-y","url":null,"abstract":"<p><p>Neuropathic pain (NP) is a chronic disease due to nerve injury, viral infections, etc. Inflammatory factors are a key part of its pathological mechanism, and NLRP3 has been widely studied in other diseases; however, its study in NP is still scarce. We analyzed genes differentially expressed in NP and normal samples using public databases. Six key markers were screened by WGCNA and a machine learning approach. The research value of key markers in NP was further verified by correlation analysis, expression analysis and validation, regulatory network construction, and molecular docking. Our results identified six reliable key markers: Lyz2, Fcgr4, Gm2a, Sumf1, Zbtb7a, and Treml2. After correlation analysis and molecular functional similarity analysis, it was concluded that Lyz2 might be a key marker of NLRP3 with greater potential in NP. Our study may find new targets for NP.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"12634-12650"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of microRNA In Situ Hybridization on Long-term Stored Human Formalin-fixed Paraffin-embedded Brain Samples from Psychiatric Patients.","authors":"Rolf Søkilde, Erik Kaadt, Lasse Sommer Kristensen, Morten Trillingsgaard Venø, Jørgen Kjems, Jens Randel Nyengaard, Boye Schnack Nielsen, Betina Elfving","doi":"10.1007/s12035-025-05077-z","DOIUrl":"10.1007/s12035-025-05077-z","url":null,"abstract":"<p><p>Here, we report that long-term stored human brain samples, formalin-fixed paraffin-embedded (FFPE) from The Brain Collection, University of Southern Denmark, Denmark ( https://www.sdu.dk/en/forskning/bridge/the-brain-collection ), can be used for in situ hybridization (ISH) analysis of selected microRNAs (miRNAs). The Human Brain Collection consists of brains from 9479 subjects who died at a Danish State Mental Hospital in the period of 1945-1982. In the present study we included tissue specimens from prefrontal cortex (PFC) and hippocampus (HIP) from 163 patients diagnosed with schizophrenia, bipolar disorder, or major depressive disorder. Initially, the Nanostring nCounter platform was used to identify miRNA candidates for ISH analysis using the miRNAscope technology. Based on the Nanostring nCounter quantifications with bulk tissue, we identified and selected 10 miRNAs from PFC (miR-9-5p, miR-29b-3p, miR-30c-5p, miR-124-3p, miR-125b-5p, miR-138-5p, miR-181a-5p, miR-224-5p, miR-302d-3p, and miR-432-5p) and 6 miRNAs from HIP (let-7a-5p, miR-7-5p, miR-124-3p, miR-127-3p, miR-145-5p and miR-149-5p). miRNAscope ISH analysis was then performed with the respective probes on 30 PFC and 30 HIP samples, respectively. In the PFC six miRNAs (miR-9-5p, miR-29b-3p, miR-124-3p, miR-125b-5p, miR-138-5p, and miR-181a-5p) were detected and four (miR-145-5p, let-7a-5p, miR-124-3p and miR-7-5p) in the HIP samples. In both brain regions miR-124-3p was the most abundantly expressed. We conclude, that the combination of the Nanostring nCounter technology and the miRNAscope analysis is a valid approach to study spatial expression of specific miRNAs in these up to 76 years old FFPE blocks. This opens a new avenue of possibilities for studying the underlying epigenetic mechanisms in mental disorders.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"12736-12746"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12433438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncRNA ZFAS1 Combined with SRSF1 Regulate CNPY2 Expression and Leads to Microglia Endoplasmic Reticulum Stress-Induced Spinal Cord Injury.","authors":"Pengcheng Chen, Zhong Huang, Yiheng Liu","doi":"10.1007/s12035-025-05080-4","DOIUrl":"10.1007/s12035-025-05080-4","url":null,"abstract":"<p><p>Spinal cord injury (SCI) has a high mortality and disability rate. Endoplasmic reticulum (ER) stress induces neuronal apoptosis and participates in the regulation of SCI. LncRNA ZFAS1 can participate in the regulation of SCI by influencing ER stress; however, its mechanism is worth further exploring. The molecular mechanism of lncRNA ZFAS1 regulating spinal cord injury was evaluated by in vitro and in vivo experiments. We established an SCI model in vitro by inducing mouse microglia (BV-2) with LPS. The regulation of SCI was verified by transfection of shRNA knockdown lncRNA ZFAS1 and CNPY2. The expression levels of related genes and proteins were detected by qPCR and western blot. The proportion of apoptosis was analyzed by flow cytometry and TUNEL staining. RIP and RNA pull down verified that lncRNA ZFAS1 combined with SRSF1 stabilized CNPY2 mRNA. It was verified that lncRNA ZFAS1 promoted ER stress and accelerated SCI injury in SCI mice model. Our results showed that the expression of lncRNA ZFAS1 and CNPY2 increased in SCI cell model, which was related to SCI injury. Knocking down lncRNA ZFAS1 or CNPY2 could inhibit ER stress and reduce apoptosis of BV-2 cells. Inhibition of lncRNA ZFAS1 in SCI mice increased the number of spinal cord neurons and ER stress response, and improved SCI injury in mice. Molecular experiments confirmed that lncRNA ZFAS1 stabilized CNPY2 mRNA by binding to SRSF1. And the lncRNA ZFAS1/CNPY2 axis was involved in regulating ER stress and apoptosis of BV-2 cells. LncRNA ZFAS1 stabilized CNPY2 by combining with SRSF1, which led to ER stress in microglia and promoted SCI. LncRNA ZFAS1 may be a potential target gene for the prevention and treatment of SCI.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"12924-12937"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differentiation of SH-SY5Y Cells into Cortical Neuron-like Cells for Tauopathy Modeling and Seeding Assays.","authors":"Alexander Devyatov, Ihor Kozlov, Viswanath Das","doi":"10.1007/s12035-025-05100-3","DOIUrl":"10.1007/s12035-025-05100-3","url":null,"abstract":"<p><p>SH-SY5Y cells are widely used as an in vitro neuronal model, yet reliable differentiation protocols tailored for tauopathy research remain limited. Effective differentiation is essential for studying tau aggregation, propagation, and neurodegenerative mechanisms. Here, we present an optimized two-step differentiation protocol for TauP301L-expressing SH-SY5Y cells that enhances neuronal maturation and tauopathy modeling, providing a physiologically relevant system for investigating tau seeding. SH-SY5Y cells expressing TauP301L-EGFP under an inducible system were differentiated using a two-step protocol consisting of retinoic acid (RA) for 72 h, followed by brain-derived neurotrophic factor (BDNF) and RA for 72 h. Differentiated neurons were then exposed to exogenous P301L tau peptide fibrils to assess their susceptibility to tau seeding and aggregation. Differentiation resulted in increased neurite outgrowth, cholinergic marker expression (ChAT upregulation, TH downregulation), and upregulation of the mature 2N4R tau isoform. Western blot analysis showed increased T22 and pSer262 tau immunoreactivity in seeded cells, consistent with tau conformational changes and pathological phosphorylation. These findings may reflect early stages of tau misfolding but do not confirm oligomer formation. Seeding also induced neurite remodeling, varicosity formation, and reduced neurite diameter-features consistent with tau-mediated pathology involving cytoskeletal changes, organelle accumulation, or axonal transport defects. This optimized differentiation protocol provides an experimentally tractable tauopathy model for investigating tau propagation and neuronal dysfunctions in a controlled human cell context. Compared to existing SH-SY5Y differentiation methods, our system provides faster neuronal maturation, controlled TauP301L induction, and enhanced tau isoform expression, making it a valuable platform for studying early tau misfolding events and therapeutic interventions in tauopathies.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"12951-12962"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12433439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Inhibition of Fatty Acid Amide Hydrolase-4 Affords Neuroprotection in a Toxic Model Induced by 6-Hydroxydopamine in Caenorhabditis elegans Nematodes.","authors":"Rubén Estrada-Valencia, Isaac Túnez, Alexey A Tinkov, Michael Aschner, Tessy López-Goerne, José Pedraza-Chaverrí, Abel Santamaría","doi":"10.1007/s12035-025-05104-z","DOIUrl":"10.1007/s12035-025-05104-z","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons. Drugs modulating the endocannabinoid system (ECS) emerge as promising tools for reducing symptomatology and/or progression of this disease. Here, the protective potential of ECS regulation against 6-hydroxydopamine (6-OHDA)-induced neuronal damage was evaluated in the nematode, Caenorhabditis elegans. First, the effect of the endocannabinoid anandamide (AEA; 1 to 100 µM) was tested in adult nematodes. As this eCB had no protective effects on the 6-OHDA-induced increased neurodegeneration, an alternative treatment was tested by exposing worms to JZL184, an inhibitor of the enzyme fatty acid amide hydrolase-4 (FAAH-4). In contrast to AEA, this compound readily induced a protective effect in dopaminergic neurons exposed to 6-OHDA, also increasing worm survival. JZL184 also improved the ability of nematodes to detect food, a behavioral task associated with an intact dopaminergic system. The protective activity induced by FAAH-4 inhibition was also confirmed using the mutant OD3609 strain, a faah-4 gene knockout nematode. This strain was more resistant to 6-OHDA compared to the wild-type N2 strain, in parameters of survival and food seeking behavior. In the CL2166 strain, pretreatment with JZL184 increased the expression of the gst-4 gene at 3 and 24 h following the exposure to 6-OHDA, indicating an antioxidant response. The effects of JZL184 (50 µM) and the endocannabinoid 2-arachidonoylglycerol (2-AG; 1-100 µM) were evaluated on 6-OHDA-induced reactive oxygen species (ROS) generation. This was based on the hypothesis that the protective effects observed following FAAH-4 inhibition may be mediated by 2-AG. Both JZL-184 and 2-AG attenuated ROS formation 24 h after 6-OHDA exposure. Altogether, these results suggest that the use of the pharmacological inhibitor of eCB degradation is effective in affording neuroprotection, also indicating that the activation of antioxidant responses mediated by the ECS is a process conserved through the evolution in the nematode.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"12984-12999"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interactive Effect of Plasma Lipidome on Neuropsychiatric Disorders: A Bidirectional Mendelian Randomization Study.","authors":"Xiao Xiao, Xiaolei Luo, Yanyun Wang, Xinmin Pan, Linbo Gao, Shanling Liu, Lin Zhang","doi":"10.1007/s12035-025-05105-y","DOIUrl":"10.1007/s12035-025-05105-y","url":null,"abstract":"<p><p>Lipid metabolism disruptions are implicated in nervous and mental disorders; plasma lipidomics show promise as diagnostic and therapeutic targets. However, clarification of causal relationships between plasma lipids and neuropsychiatric disorders (NPDs) remains unclear. We employed bidirectional Mendelian randomization (MR) to examine causal links between 179 plasma lipids and 17 NPDs. Significant associations in the forward MR were further investigated using linkage disequilibrium score regression (LDSC), Bayesian colocalization (COLOC) analysis, and mediation analysis. Forward MR revealed sterol ester (27:1/16:1) and diacylglycerol (16:0_18:2) elevations may increase anorexia nervosa (AN) risk, while sphingomyelin (d36:2) elevation potentially lowers it. LDSC analysis showed no substantial genetic link between the three lipids and AN, while low posterior probability of hypothesis 4 from COLOC test disputed the presence of shared variants. Besides, AN risk elevated by sterol ester's (27:1/16:1) was suggested to mediate through C-X-C chemokine 10 downregulation. In the reverse MR, we uncovered varied causal ties: ADHD increased sterol ester (27:1/20:3), phosphatidylcholines (18:0_20:3, 18:1_20:3); Alzheimer's disease lowered phosphatidylcholine (O - 18:1_20:3); Ischemic stroke tied to less phosphatidylcholine (16:0_0:0); Obsessive-compulsive disorder exhibited a dual effect, upregulating phosphatidylcholine (16:1_18:0) and downregulating sterol ester (27:1/22:6); Parkinson's disease linked to less diacylglycerol (18:1_18:3); Schizophrenia tied to more triacylglycerols (48:0,51:1); Migraine reduced sterol ester (27:1/20:2). These insights reveal causal dynamics between plasma lipids and neuropsychiatric conditions. Our findings extend the causal landscape linking the plasma lipidome to NPDs, offering insights for the discovery of novel biomarkers and therapeutic targets in these diseases.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"12894-12906"},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}