Neurobiology of Disease最新文献

{"title":"The temporal onset of associations of cortical proteins with cognitive resilience vary during late life","authors":"Andrea R. Zammit ,&nbsp;Tianhao Wang ,&nbsp;Lei Yu ,&nbsp;Shahram Oveisgharan ,&nbsp;Vladislav A. Petyuk ,&nbsp;Philip L. De Jager ,&nbsp;Julie A. Schneider ,&nbsp;David A. Bennett ,&nbsp;Aron S. Buchman","doi":"10.1016/j.nbd.2025.106927","DOIUrl":"10.1016/j.nbd.2025.106927","url":null,"abstract":"<div><h3>Background</h3><div>Cortical proteins associated with cognitive resilience have been identified but their temporal onset in older adults is unknown. We present a multistage approach to first identify cortical proteins associated with cognitive resilience and then examine their associated temporal onset.</div></div><div><h3>Methods</h3><div>We used data from a subset of 1088 decedents from two cohort-studies who had selected reaction monitoring proteomics from the dorsolateral prefrontal cortex, and at least 3 cognitive assessments. Cognition was assessed using a composite derived from 19 tests. We first used linear mixed-effects models to identify cortical proteins associated with cognitive resilience. We then used functional mixed-effects models to examine non-linear associations between proteins and cognitive resilience to identify their temporal onset.</div></div><div><h3>Results</h3><div>Mean age at death was 90 years (SD = 6.4); 69 % were female. On average, cognition started to decline at around 15 years before death, with accelerated decline in the last 7 years. We identified 40 proteins associated with cognitive resilience, of which 17 proteins also showed non-linear associations. Non-linear associations indicated that higher levels of 10 proteins were associated with slower cognitive decline between 23 and 4 years before death. In contrast, higher levels of 7 proteins were associated with faster decline only within the last 7 years before death.</div></div><div><h3>Conclusions</h3><div>Cognitive resilience proteins are differentially related to late-life cognitive aging; the onset of proteins that maintain cognition may begin many years before the onset of proteins that hasten cognitive decline. The temporal onset of cognitive resilience proteins may be crucial for timing efficacious interventions.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106927"},"PeriodicalIF":5.1,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143891108","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":"Sex-biased zinc responses modulate ribosomal protein expression, protein synthesis and social defects in Cttnbp2 mutant mice","authors":"Yu-Lun Fang ,&nbsp;Tzu-Li Yen ,&nbsp;Hou-Cheng Liu,&nbsp;Ting-Fang Wang,&nbsp;Yi-Ping Hsueh","doi":"10.1016/j.nbd.2025.106932","DOIUrl":"10.1016/j.nbd.2025.106932","url":null,"abstract":"<div><div>Autism spectrum disorders (ASD) are neurodevelopmental conditions influenced by genetic mutations, dietary factors, and sex-specific mechanisms, yet the interplay of these factors remains elusive. Here, we investigate the sex-biased responses of mutant mice carrying an ASD-associated mutation in <em>Cttnbp2</em> to dietary zinc supplementation using behavioral assays, proteomic and bioinformatic analyses, and puromycin pulse labeling to assess protein synthesis. Our results demonstrate that zinc supplementation enhances ribosomal protein expression and protein synthesis and increases the density and size of dendritic spines in male <em>Cttnbp2</em> mutant mice, alleviating male-biased social deficits. Analyses of neuronal cultures further revealed that neurons, not astrocytes, respond to zinc to enhance protein synthesis. In contrast, female <em>Cttnbp2</em> mutants exhibit resilience to differential zinc intake, even under zinc deprivation. Elevated mTOR phosphorylation and increased protein levels of translational initiation factors in female brains may provide a protective mechanism, reducing their sensitivity to zinc deficiency. <em>Cttnbp2</em> mutations heighten male vulnerability to zinc deprivation, impairing social behaviors. These findings highlight zinc-regulated ribosomal protein expression and protein synthesis as critical mediators of sex-specific ASD phenotypes, offering new insights into dietary interventions.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106932"},"PeriodicalIF":5.1,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890964","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":"Genetic neurocognitive profile of autism unveiled with gene transcription","authors":"Yingxing Zhang ,&nbsp;Fangfang Li ,&nbsp;Hongli Wu ,&nbsp;Wei Du ,&nbsp;Jianhua Shu ,&nbsp;Anqing Wang ,&nbsp;Chunsheng Xu ,&nbsp;Chuanfu Li ,&nbsp;Ya Wang ,&nbsp;Sheng Hu","doi":"10.1016/j.nbd.2025.106925","DOIUrl":"10.1016/j.nbd.2025.106925","url":null,"abstract":"<div><div>How neurocognitive processes elaborate phenotypic heterogeneity within autism spectrum disorder (ASD) remains unknown. Applying the principal component analysis to the Neurosynth database, we established neurocognitive profiles to characterize the phenotypic heterogeneity of ASD, revealing a cortical hierarchical axis that separates the temporal cortex from other networks. By integrating neurocognitive profiles with transcriptomic data, we found that gene sets shaping the patterns of neurocognitive profiles are enriched in ASD-related biological processes and ASD pathogenic risk. Using a data-driven approach, we identified a topographic network for ASD, comprising the temporal, frontal, somatosensory, and visual cortices, with its transcriptomic signatures differentiating between regions over neurodevelopment. Additionally, functional reorganization in ASD within the topographic network has occurred with the temporal cortex as the central node. Collectively, our results reveal spatially covarying transcriptomic and neurocognitive profiles, emphasizing the influence of functional reorganization and its underlying genetic mechanism on phenotypic heterogeneity in ASD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"210 ","pages":"Article 106925"},"PeriodicalIF":5.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143888091","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":"Integrated multi-omics insight into the molecular networks of oxidative stress in triggering multiple sclerosis","authors":"Yudi Xu ,&nbsp;Xiaowei Zhang ,&nbsp;Yuyuan Zhang ,&nbsp;Hongxuan Ma ,&nbsp;Zhaokai Zhou ,&nbsp;Hongzhuo Qin ,&nbsp;Huimin Liu ,&nbsp;Xinwei Han","doi":"10.1016/j.nbd.2025.106929","DOIUrl":"10.1016/j.nbd.2025.106929","url":null,"abstract":"<div><div>Oxidative stress (OS) is a key pathophysiological mechanism in multiple sclerosis (MS). However, the underlying mechanisms by which OS triggered MS remain unknown. To identify potential causal targets of 1216 OS-related genes for MS, a summary-data-based Mendelian randomization (SMR) method was applied. Given that genes can exert their biological functions through different omics levels, the multi-omics SMR integrating expression, methylation, and protein quantitative trait loci (eQTL, mQTL, and pQTL) of OS-related genes from blood and brain tissues was utilized. Bayesian colocalization test was conducted to examine potential regulatory mechanisms of QTL risk variation in MS. To verify the robustness of our results, we validated these findings in FinnGen cohort. Furthermore, the QTL evidence levels, colocalization findings, and replication cohort results were integrated and potential target genes were categorized into three levels. Consequently, three genes (<em>BACH2</em>, <em>TRAF3</em>, and <em>MAPK3</em>) were identified as potential contributors to MS in blood, and four genes (<em>HMGCL</em>, <em>TSFM</em>, <em>TRAF3</em> and <em>HLA-B</em>) were identified as potential contributors to MS in brain tissue. Additionally, <em>HMGCL</em> and <em>TSFM</em> from brain tissue were supported by first-level evidence related to MS and were validated via in vitro experiments. This research not only contributed to fundamental research of OS in MS but also supported the identification of potential targets for clinical interventions in MS.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"210 ","pages":"Article 106929"},"PeriodicalIF":5.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874064","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":"Oligodendrocyte myelin glycoprotein impairs dendritic arbors via schizophrenia risk gene Trio","authors":"Euan Parnell ,&nbsp;Jessica M. Christiansen ,&nbsp;Michelle A. Spratt ,&nbsp;Shelby Ruiz ,&nbsp;Matthew L. Macdonald ,&nbsp;Peter Penzes ,&nbsp;Robert A. Sweet ,&nbsp;Melanie J. Grubisha","doi":"10.1016/j.nbd.2025.106928","DOIUrl":"10.1016/j.nbd.2025.106928","url":null,"abstract":"<div><div>During adolescence, a critical developmental epoch coincident with the emergence of clinical symptoms of schizophrenia, cerebral cortical dendritic growth shifts from a rapid phase, reaching equilibrium. Oligodendrocyte Myelin Glycoprotein (OMGp) expression peaks during adolescence and has a known role in regulating dendritic stabilization. However, the precise signaling pathways transduced by OMGp are unknown. To identify these pathways, we performed unbiased phospho-proteomic analysis after OMGp stimulation, revealing 2991 phosphorylated proteins. Interestingly, several schizophrenia risk genes were identified as phospho-targets, including the potent risk factor Trio, which has a known role in regulating neurite outgrowth and the cytoskeleton through its dual Rac/RhoA catalytic domains. Phosphomimetic and phosphonull Trio9 constructs were employed to assess the functional role of OMGp-mediated phosphorylation at a novel phosphosite – Ser1258. Phosphomimetic Trio9 was deficient in Rac1 catalytic activity and induced loss of dendritic length and complexity compared to wild type protein. Moreover, phosphonull constructs blocked the OMGp-induced impairments in dendritic length and complexity. Together, these results highlight the ability of OMGp to regulate dendritic architecture by potently inhibiting the Rac1 catalytic activity of Trio through phosphorylation. These results provide a potential mechanism contributing to the emergence of neuronal structural dysfunction and schizophrenia symptomology during adolescence.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106928"},"PeriodicalIF":5.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890963","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":"Unraveling Parkinson's disease motor subtypes: A deep learning approach based on spatiotemporal dynamics of EEG microstates","authors":"Lin Meng ,&nbsp;Deyu Wang ,&nbsp;Jun Ma ,&nbsp;Yu Shi ,&nbsp;Hongbo Zhao ,&nbsp;Yanlin Wang ,&nbsp;Qingqing Shi ,&nbsp;Xiaodong Zhu ,&nbsp;Dong Ming","doi":"10.1016/j.nbd.2025.106915","DOIUrl":"10.1016/j.nbd.2025.106915","url":null,"abstract":"<div><h3>Background</h3><div>Despite prior studies on early-stage Parkinson’s disease (PD) brain connectivity and temporal patterns, differences between tremor-dominant (TD) and postural instability/gait difficulty (PIGD) motor subtypes remain poorly understood. Our study aims to understand the contribution of altered brain network dynamics to heterogeneous motor phenotypes in PD for improving personalized treatment.</div></div><div><h3>Methods</h3><div>Electroencephalography (EEG) microstate dynamics were firstly used to capture spatiotemporal brain network changes. A deep learning model was developed to classify PD motor subtypes where spatial variability and electrode location data were incorporated into the analysis.</div></div><div><h3>Results</h3><div>Compared to healthy individuals, both PD-TD and PD-PIGD patients showed increased local segregation of brain regions. The PD-PIGD subtype had more severe and extensive disorganization in microstate A dynamics, suggesting greater disruption in auditory and motor-related networks. Incorporating spatial information significantly improved the accuracy of subtype classification, with an AUC of 0.972, indicating that EEG microstate dynamic spatial patterns reflect distinct PD motor pathologies. The increased spatial variability in the PD-PIGD group was more closely associated with motor impairments.</div></div><div><h3>Conclusions</h3><div>This study presents a novel framework for differentiating PD motor subtypes and emphasizes dynamic brain network features as potential markers for understanding motor symptom variability in PD, which may contribute to the development of personalized treatment strategies.</div><div><strong>Trial registration:</strong> ChiCTR2300067657.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"210 ","pages":"Article 106915"},"PeriodicalIF":5.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868504","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":"Early neural dysfunction reflected in degraded auditory cortex responses in pre-regression heterozygous Mecp2 rats","authors":"Yuko Tamaoki ,&nbsp;Samantha L. Kroon ,&nbsp;Brendan M. Williams ,&nbsp;Jonathan R. Riley ,&nbsp;Crystal T. Engineer","doi":"10.1016/j.nbd.2025.106926","DOIUrl":"10.1016/j.nbd.2025.106926","url":null,"abstract":"<div><div>Rett syndrome, a genetic disorder caused by mutations in the X-linked <em>Mecp2</em> gene, is characterized by typical early development followed by rapid developmental regression between 6 and 18 months of age. Affected individuals exhibit seizures, cognitive impairments, motor deficits, and difficulties in speech-language processing. Post-regression rodent models of Rett syndrome have been observed to follow similar regression, presenting sensory processing difficulties during auditory discrimination tasks, as well as degraded auditory cortical responses. However, little is known about the auditory processing prior to the onset of regression symptoms. This study documents primary auditory cortex responses to sounds in pre-regression heterozygous <em>Mecp2</em> rats compared to age-matched wild-type controls. Pre-regression <em>Mecp2</em> rats exhibited weaker and delayed cortical responses to speech sounds, alterations in the temporal processing of rapidly presented sounds, and an overrepresentation of high-frequency tones in conjunction with a reduction in the cortical representation of low-frequency tones. Despite these impairments, pre-regression <em>Mecp2</em> rats demonstrated intact neural classifier performance for consonant discrimination, which is consistent with the high accuracy these pre-regression <em>Mecp2</em> rats exhibit for a behavioral consonant discrimination task. These findings reveal that cortical deficits in <em>Mecp2</em> rats emerge before behavioral regression. Insights derived from this study expand upon the current understanding of the progression of sensory processing deficits in Rett syndrome and other neurodevelopmental disorders and lay the groundwork for the development of therapeutics for this population.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"210 ","pages":"Article 106926"},"PeriodicalIF":5.1,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874126","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":"Intersecting impact of CAG repeat and huntingtin knockout in stem cell-derived cortical neurons","authors":"Jennifer T. Stocksdale ,&nbsp;Matthew J. Leventhal ,&nbsp;Stephanie Lam ,&nbsp;Yu-Xin Xu ,&nbsp;Yang Oliver Wang ,&nbsp;Keona Q. Wang ,&nbsp;Reuben Thomas ,&nbsp;Zohreh Faghihmonzavi ,&nbsp;Yogindra Raghav ,&nbsp;Charlene Smith ,&nbsp;Jie Wu ,&nbsp;Ricardo Miramontes ,&nbsp;Kanchan Sarda ,&nbsp;Heather Johnston ,&nbsp;Min-Gyoung Shin ,&nbsp;Terry Huang ,&nbsp;Mikelle Foster ,&nbsp;Mariya Barch ,&nbsp;Naufa Amirani ,&nbsp;Chris Paiz ,&nbsp;Leslie M. Thompson","doi":"10.1016/j.nbd.2025.106914","DOIUrl":"10.1016/j.nbd.2025.106914","url":null,"abstract":"<div><div>Huntington's Disease (HD) is caused by a CAG repeat expansion in the gene encoding huntingtin (HTT). While normal HTT function appears impacted by the mutation, the specific pathways unique to CAG repeat expansion versus loss of normal function are unclear. To understand the impact of the CAG repeat expansion, we evaluated biological signatures of HTT knockout (<em>HTT</em> KO) versus those that occur from the CAG repeat expansion by applying multi-omics, live cell imaging, survival analysis and a novel feature-based pipeline to study cortical neurons (eCNs) derived from an isogenic human embryonic stem cell series (RUES2). <em>HTT</em> KO and the CAG repeat expansion influence developmental trajectories of eCNs, with opposing effects on growth. Network analyses of differentially expressed genes and proteins associated with enriched epigenetic motifs identified subnetworks common to CAG repeat expansion and <em>HTT</em> KO that include neuronal differentiation, cell cycle regulation, and mechanisms related to transcriptional repression, and may represent gain-of-function mechanisms that cannot be explained by <em>HTT</em> loss of function alone. A combination of dominant and loss-of-function mechanisms are likely involved in the aberrant neurodevelopmental and neurodegenerative features of HD that can help inform therapeutic strategies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"210 ","pages":"Article 106914"},"PeriodicalIF":5.1,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878578","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":"Contributions of major tau kinase activation and phospho-tau accumulation to cortical and hippocampal tangle formation and cognition in older adults","authors":"Elena Hernández-Hernández ,&nbsp;Vladislav A. Petyuk ,&nbsp;Júlia Valor-Blanquer ,&nbsp;Fernando Yáñez-Gómez ,&nbsp;Alasdair M. Barr ,&nbsp;Philip L. De Jager ,&nbsp;Er-Yun Chen ,&nbsp;Sue E. Leurgans ,&nbsp;Julie A. Schneider ,&nbsp;David A. Bennett ,&nbsp;William G. Honer ,&nbsp;M. Julia García-Fuster ,&nbsp;Alfredo Ramos-Miguel","doi":"10.1016/j.nbd.2025.106924","DOIUrl":"10.1016/j.nbd.2025.106924","url":null,"abstract":"<div><div>Aberrant activation of tau kinases (tauK) has been proposed as a major step in tau hyperphosphorylation and misfolding, and subsequent formation of neurofibrillary tangles (NFT) in Alzheimer's disease (AD). However, evidence of tauK hyperactivation in actual AD brains is scarce and inconsistent, and their role in age-related cognitive decline remains undocumented. We evaluated activated/inhibited species of CDK5/p35/p25, GSK3α/β, and ERK1/2 as well as ten tau/phospho-tau (ptau) peptides (mapping Ser²⁰², Thr²¹⁷, Ser²⁶², Ser³⁰⁵, and Ser⁴⁰⁴ phospho-residues) by Western blot or selected reaction monitoring proteomics, respectively, in postmortem dorsolateral prefrontal cortex (DLPFC) and hippocampal samples of 150 participants from the Rush Memory and Aging Project (MAP). Regression models and mediation analyses assessed the contributions of these variables to tau phosphorylation, NFT deposition and antemortem cognitive status of MAP participants. Surprisingly, greater p25 and p35 (indices for CDK5 activation) and lower pSer^21/9-GSK3α/β (inhibited species) immunodensities were associated with lower ptau peptide amounts. Individuals with higher p25 cortical densities displayed better cognitive outcomes, particularly working memory. Statistical mediation analyses indicated that the beneficial effect of CDK5/p25 on cognition was mediated by lower densities of phospho-Thr²¹⁷-tau and NFT deposition in DLPFC, and also identified Thr²¹⁷ and Ser²⁶² as the ptau sites with greatest influence in both NFT accumulation and cognitive impairment. The present data suggest that tau hyperphosphorylation, tangle deposition, and the subsequent cognitive impairment do not rely on aberrant activation of major tauKs. Additionally, novel evidence was provided for the beneficial contribution of cortical CDK5/p25 to the maintenance of working memory.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"210 ","pages":"Article 106924"},"PeriodicalIF":5.1,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143852178","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":"Early plasma ceramide and sphingomyelin levels reflect APOE genotype but not familial Alzheimer's disease gene mutations in female 5xFAD mice, with brain-region specific sphingolipid alterations","authors":"Daan van Kruining ,&nbsp;Mario Losen ,&nbsp;Jonas Dehairs ,&nbsp;Johannes V. Swinnen ,&nbsp;Etienne Waelkens ,&nbsp;Maarten Honing ,&nbsp;Pilar Martinez-Martinez","doi":"10.1016/j.nbd.2025.106923","DOIUrl":"10.1016/j.nbd.2025.106923","url":null,"abstract":"<div><div>Pathophysiological changes associated with Alzheimer's disease (AD) begin decades before dementia onset, with age and APOE ε4 genotype as major risk factors [1–4]. Primary risk factors for developing AD include aging and number of copies of the apolipoprotein E (APOE) ε4 allele. Altered sphingolipid metabolism is increasingly implicated in early AD. However, the relationship between early plasma and brain sphingolipid changes—particularly in the context of APOE genotype—remains poorly defined.</div><div>In this study, we analyzed plasma and brain sphingolipid profiles in transgenic AD mice carrying human APOE3 or APOE4 variants, with or without familial AD mutations (E3FAD and E4FAD). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we assessed 110 sphingolipid species across four major classes (ceramides (Cers), hexosylceramides (HexCers), lactosylceramides (LacCers), and sphingomyelins (SMs)) at 2, 4, and 6 months in plasma and at 6 months in brain tissue in the cortex, hippocampus, striatum, and cerebellum.</div><div>Our results demonstrate that early plasma sphingolipid alterations are largely driven by APOE genotype rather than AD pathology. Specifically, APOE4 carriers showed significant increases in SM species and reductions in Cer species compared to APOE3 carriers, independent of age or AD genotype. Brain lipid profiles showed minimal changes across genotypes after region correction. However, combined <em>p</em>-value analyses revealed APOE- and EFAD-dependent differences in the composition of primarily cortical sphingolipids. ROC analyses demonstrated high discriminative power of plasma sphingolipids for APOE, but not for AD genotype.</div><div>These findings suggest that early plasma lipid profiles in female 5xFAD mice are more strongly influenced by APOE genotype than by overt AD pathology, potentially reflecting systemic pathways linked to APOE4-associated AD risk, while early disease-associated changes in the brain appear to be subtle and region-specific. These results underscore the importance of accounting for APOE genotype in early-stage AD lipidomic studies and in the interpretation of peripheral lipid biomarkers.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"210 ","pages":"Article 106923"},"PeriodicalIF":5.1,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868505","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}