Journal of Molecular Neuroscience最新文献

{"title":"Genetic Variations in the Dopaminergic Signaling Pathways and Their Implications for Antipsychotics Pharmacogenetics","authors":"Holiness S. A. Olasore,&nbsp;Matthew O. Olawale,&nbsp;Damilare P. Asiwaju,&nbsp;Anthony A. Olashore","doi":"10.1007/s12031-026-02505-0","DOIUrl":"10.1007/s12031-026-02505-0","url":null,"abstract":"<div><p>The role of neurotransmitter systems in the pathology and management of psychiatric disorders is well documented. Targeting these systems has remained the mainstay of standard pharmacological interventions, with typical and atypical antipsychotics demonstrating effectiveness in reducing both positive and negative symptoms of schizophrenia. However, their clinical efficacy and side effect profiles vary among individuals due to genetic differences. This review aims to examine key genetic variants in the dopaminergic neurotransmitter system that influence antipsychotic response, with particular emphasis on clinically relevant single-nucleotide polymorphisms (SNPs), to support improved treatment outcome prediction and precision psychiatry. Polymorphisms in genes encoding dopamine receptors, transporters, and metabolising enzymes have been associated with variability in antipsychotic efficacy and susceptibility to adverse effects. Across multiple studies, the catechol-O-methyltransferase (COMT) Val158Met (rs4680) polymorphism and the dopamine D2 receptor/ANKK1 <i>Taq</i>1A (rs1800497) variant are among the most consistently reported genetic contributors to variability in dopamine signalling, receptor availability, and drug metabolism. These variants have been linked to differential therapeutic outcomes, including improved response in some treatment-resistant patients, as well as an increased risk of extrapyramidal symptoms, hyperprolactinaemia, and metabolic disturbances. These findings indicate that genetic variation in the dopaminergic system is a key contributor to differences in antipsychotic response. Integrating pharmacogenomic information in clinical practice may enhance personalised treatment strategies, reduce trial-and-error prescribing, and improve long-term outcomes in schizophrenia. </p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147519796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Repurposing of Nilotinib and Radotinib as SIRT2 Inhibitors for Neurodegenerative Diseases","authors":"Taghreed A. Majrashi,&nbsp;Mohammad Y. Alshahrani,&nbsp;Moady Ahmad Asiri,&nbsp; Zia-Ul-Sabah,&nbsp;Mohammad Abohassan,&nbsp;Devesh U. Kapoor,&nbsp;Shadma Wahab","doi":"10.1007/s12031-026-02511-2","DOIUrl":"10.1007/s12031-026-02511-2","url":null,"abstract":"<div>\u0000 \u0000 <p>Neurodegenerative diseases (NDs) including Alzheimer’s and Parkinson’s disease involve progressive neuronal death, and current treatments are unsatisfactory. Sirtuin-2 (SIRT2), a NAD⁺ dependent deacetylase with roles in microtubule dynamics and redox regulation, has been suggested as potential druggable target for neurodegeneration. As part of this work, we conducted a virtual screening using the FDA-approved drugs library against the SIRT2 protein to discover potential inhibitors more potent than SirReal2. The binding energy and its interaction study concluded that Nilotinib and Radotinib exhibited higher bindings (-13.2 kcal/mol and  -12.8 kcal/mol) than SirReal2 (-11.8 kcal/mol) through the formation of crucial interactions with the catalytic residues located at binding and active sites. PASS analysis revealed anti neurodegenerative potential for both drugs. Long-time scale molecular dynamics (500 ns) simulations investigated structural stability of SIRT2-drug complexes with reduced RMSD and RMSF values compared to protein-ligand complexes from SirReal2 together with the maintained compactness within the protein. Principal component and free energy landscape analysis revealed that Nilotinib, Radotinib bound to SIRT2 in lower-energy conformation with limited movement than the higher dynamic fluctuations induced by SirReal2. Moreover, MMPBSA and DFT calculation also investigate the binding stability complexes. Taken together, our results demonstrate Nilotinib and Radotinib as potential lead drugs for repurposing toward the discovery of novel inhibitors of SIRT2 with therapeutic implications in neurodegenerative diseases. These crucial findings strongly recommended for further experimental validation through in vitro and in vivo analysis.</p>\u0000 </div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Evidence Supports a Potential Role of WTAP-related m6A Regulation in Vascular Dementia: Insights from Mendelian Randomization and Multi-omics Analyses","authors":"Wancheng Zheng,&nbsp;Jin Qiu,&nbsp;Dehai Xian,&nbsp;Kaiwen Yang","doi":"10.1007/s12031-026-02510-3","DOIUrl":"10.1007/s12031-026-02510-3","url":null,"abstract":"<div><p>Vascular dementia (VAD) is a major cause of cognitive decline, yet its molecular determinants remain incompletely understood. Emerging evidence suggests that N6-methyladenosine (m6A) RNA modification may influence cerebrovascular biology; however, its potential causal relevance to VAD has not been systematically evaluated in human genetic studies. We conducted Mendelian randomization (MR) using m6A-related expression quantitative trait loci (eQTLs) as instrumental variables and FinnGen VAD GWAS data as the outcome. Significant signals were further examined using summary-data-based Mendelian randomization (SMR) and differential expression analysis of GSE122063. For the bulk transcriptome dataset (GSE122063), samples were treated as independent observations based on dataset structure (no repeated multi-region sampling per subject), and linear modeling was performed using standard normalization procedures. Mediation by 473 gut microbial taxa was evaluated using two-step MR. Weighted gene co-expression network analysis (WGCNA), single-cell RNA sequencing (GSE282111), and phenome-wide association studies (PheWAS) were applied to explore co-expression patterns, cellular distribution, and phenotypic associations. Across MR models, genetically predicted WTAP expression was associated with increased VAD risk (IVW OR = 1.28, 95% CI: 1.14–1.45, P = 4.9 × 10⁻⁵). SMR analysis provided supportive evidence for this association (OR = 1.26, P = 0.0126), and GEO data indicated higher WTAP expression in VAD brain tissue. Mediation analysis suggested partial indirect effects through gut microbial taxa, including Halomonadaceae (38.8%) and Bacillus velezensis (19.0%). WGCNA identified a VAD-related blue module (cor = 0.45, P = 3 × 10⁻⁵), enriched in the Apelin signaling pathway. Single-cell analysis showed cell-type–specific WTAP expression patterns, particularly in vascular smooth muscle cells and neurons. PheWAS revealed associations with neurological, inflammatory, and lipoprotein(a)-related traits. This integrative genetic and transcriptomic analysis provides convergent evidence supporting a potential role of WTAP in VAD susceptibility and suggests links between m6A regulation, gut microbiota, and cerebrovascular biology. These findings generate testable hypotheses for future experimental studies but require functional validation to confirm underlying mechanisms.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single Nucleotide Polymorphisms in Stroke: Evidence Across Susceptibility, Prognosis, and Recurrence; A Systematic Review","authors":"Nicholas Aderinto,&nbsp;Ibiyinka Daramola,&nbsp;Chiamaka Norah Ezeagu,&nbsp;Gbolahan Olatunji,&nbsp;Emmanuel Kokori,&nbsp;Bonaventure Michael Ukoaka,&nbsp;Adetola Emmanuel Babalola,&nbsp;Olamide Asifat,&nbsp;Aditya Gaur,&nbsp;Israel Charles Abraham,&nbsp;Faisal Hamed Aljamea","doi":"10.1007/s12031-026-02503-2","DOIUrl":"10.1007/s12031-026-02503-2","url":null,"abstract":"<div>\u0000 \u0000 <p>Stroke is a leading cause of global morbidity and mortality. Genetic variation, particularly single nucleotide polymorphisms (SNPs), has been implicated not only in stroke susceptibility but also in post-stroke outcomes and recurrence. However, evidence remains fragmented across populations, stroke subtypes, and clinical endpoints. We conducted a systematic review in accordance with PRISMA guidelines, searching PubMed, Scopus, Web of Science, Embase, Cochrane Library, and Google Scholar through January 2025. Eligible studies included case–control, cohort, genome-wide association, and Mendelian randomization studies examining associations between SNPs and incident stroke risk, post-stroke outcomes, or recurrence. Data were extracted on study design, population, genetic variants, and effect estimates. Study quality was assessed using the Newcastle–Ottawa Scale, supplemented by qualitative consideration of genetic-study–specific biases. Twenty-seven studies were included, encompassing diverse populations and stroke-related outcomes. SNPs in genes related to inflammation (e.g., <i>TNF-α</i>, <i>HMGB1</i>), lipid metabolism (<i>ANGPTL4</i>, <i>DIAPH1</i>), oxidative stress (<i>MTHFR</i>), and regulatory RNAs (<i>MIAT</i>, microRNAs) were associated with stroke susceptibility, subtype-specific risk, post-stroke recovery, or recurrence. Associations varied substantially by study design, population, and outcome, with most findings derived from candidate-gene studies and limited independent replication. Genetic variants across multiple biological pathways are associated with stroke-related phenotypes, including susceptibility, prognosis, and recurrence. However, heterogeneity of outcomes and study designs limits causal inference and clinical translation. Larger multi-ethnic studies with replication and functional validation are required before SNP-based risk stratification can be routinely applied.</p>\u0000 </div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 2","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147466367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic High-Carbohydrate And High-Fat Diet-Induced Metabolic Syndrome Leads To Adrenal Dysfunction, Altered Dendritic Morphology In Limbic Regions, And Anxiety-Like Behaviors In Male Rats","authors":"Samuel Treviño,&nbsp;Estefania Fuentes,&nbsp;Berenice Venegas,&nbsp;Guadalupe Muñoz-Arenas,&nbsp;Rubén A. Vázquez-Roque,&nbsp;Fabián Galindo-Ramírez,&nbsp;Everardo Avelino-Cruz,&nbsp;Gonzalo Flores,&nbsp;Jorge Guevara,&nbsp;Alfonso Díaz","doi":"10.1007/s12031-026-02501-4","DOIUrl":"10.1007/s12031-026-02501-4","url":null,"abstract":"<div>\u0000 \u0000 <p>Metabolic syndrome (MS) represents a major global health problem affecting a large proportion of the population. The improper management of peripheral carbohydrates and lipids leads to behavioral changes in neurons of the limbic brain. This work studied male rats that received diets high in carbohydrates, lipids, and their combination for ninety days. The study examined how peripheral metabolic changes and hypothalamic-pituitary-adrenal (HPA) axis alterations affect dendritic structure in limbic brain regions, thereby inducing anxiety-related behavioral responses. Our results show that male rats develop MS after consuming diets high in fat, carbohydrates, and their mixture for an extended period. These diets after the normal function of the HPA axis, leading to increased anxiety symptoms and reduced dendritic growth in limbic areas. This is accompanied by increased caspase-3 immunoreactivity and decreased cell viability. Therefore, it is suggested that diets high in carbohydrates or fats are a critical factor that could induce adrenal stress that damages dendrites and accelerates neurodegeneration, resulting in anxiety-related behavioral changes.</p>\u0000 </div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12031-026-02501-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147441922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TASP1-Related Suleiman–El-Hattab Syndrome: The First Genetically Confirmed Case in Iran Accompanied by a Comprehensive Literature Review","authors":"Narges Mashayekhi,&nbsp;Alireza Zangooie,&nbsp;Reza Asgari,&nbsp;Morteza Heidari,&nbsp;Ali Nikkhah,&nbsp;Shiva Bayat,&nbsp;Seyyed Mohammad Kahani,&nbsp;Mahmoud Reza Ashrafi","doi":"10.1007/s12031-026-02507-y","DOIUrl":"10.1007/s12031-026-02507-y","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;p&gt;Suleiman–El-Hattab syndrome (SULEHS; OMIM #618674) is an ultra-rare autosomal recessive multisystem neurodevelopmental disorder caused by biallelic loss-of-function variants in &lt;i&gt;TASP1&lt;/i&gt;, with a characteristic combination of global developmental delay/intellectual disability, distinctive craniofacial dysmorphism, recurrent infections, congenital anomalies, and a typically cheerful affect. Because fewer than ten molecularly confirmed individuals have been reported, the phenotypic spectrum and neuroradiologic variability remain incompletely defined. We describe the first genetically confirmed Iranian patient with a clinical phenotype suggestive of SULEHS, including microcephaly, failure to thrive, syndromic facial features, neurodevelopmental delay (NDD), recurrent pneumonias, cardiac and genitourinary anomalies, hearing impairment, seizures, and a happy demeanor with drooling. Brain MRI demonstrated ventriculomegaly and a posterior fossa malformation consistent with a Dandy–Walker variant. Conventional cytogenetics and array-CGH were uninformative; therefore, whole-exome sequencing (WES) with segregation analysis was performed. In parallel, we conducted a targeted literature review and systematically compared our patient’s clinical and imaging findings with eight previously reported molecularly confirmed cases. WES identified a novel homozygous &lt;i&gt;TASP1&lt;/i&gt; variant (NM_017714.3:c.358 A &gt; G; p.Met120Val), classified as a variant of uncertain significance (VUS), with both parents confirmed as heterozygous carriers. Comparative analysis across the eight published cases and our patient demonstrated substantial overlap in core features—microcephaly, failure to thrive, typical craniofacial gestalt (e.g., thick highly arched eyebrows with synophrys, hypertelorism, periorbital fullness, ear anomalies), recurrent respiratory infections, cardiovascular anomalies, developmental delay/intellectual disability (DD/ID), happy demeanor, and drooling—while several commonly reported findings (e.g., epicanthus, thick eyelids, thick lower lip vermilion, lumbosacral hirsutism, feeding difficulties, hypotonia) were absent in our patient. Neuroimaging across prior cases included corpus callosum abnormalities, ventriculomegaly, encephalomalacia, and posterior fossa malformations; in our case, only ventriculomegaly and posterior fossa malformation were present. This report expands the geographic and clinical spectrum of SULEHS by documenting the ninth reported molecularly confirmed case and the first from Iran, and it further delineates phenotypic and neuroradiologic heterogeneity by showing ventriculomegaly with a posterior fossa malformation consistent with a Dandy–Walker variant. In our patient, conventional genetic testing (karyotype and array-CGH) was uninformative, whereas WES identified a novel homozygous &lt;i&gt;TASP1&lt;/i&gt; classified as VUS with parental carrier segregation; although functional validation is still required, th","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147441924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network-Based Prioritization of Network-Peripheral Gene Modules in Autism Spectrum Disorder Using Integrative Transcriptomic and Proteomic Data","authors":"Walaa Mohammedsaeed,&nbsp;Mohammed Alharbi","doi":"10.1007/s12031-026-02502-3","DOIUrl":"10.1007/s12031-026-02502-3","url":null,"abstract":"<div>\u0000 \u0000 <p>Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with complex genetic and molecular architecture. While numerous ASD-associated genes have been identified, how distributed gene modules, particularly network-peripheral genes, contribute to ASD-related biological processes remains incompletely understood. Here, <i>peripheral gene modules</i> refer to genes located at the topological periphery of molecular interaction networks, characterized by non-hub or lower global centrality yet functional connectivity within ASD-relevant pathways, rather than to peripheral tissues or blood-derived samples. We applied an integrative in silico framework combining bulk transcriptomic, proteomic, and single-cell RNA-seq datasets derived from human brain cortex samples. Network-based analyses were performed using STRING and Cytoscape to identify functionally coherent gene modules, with deliberate prioritization of network-peripheral nodes based on distribution-based closeness centrality metrics. Functional enrichment analyses were conducted using Pathway Commons and KEGG, and cell-type-specific expression patterns were evaluated using published single-cell transcriptomic data. Network analysis identified peripheral gene modules associated with synaptic vesicle trafficking, nuclear–cytoplasmic transport, RNA surveillance, ciliary function, apoptosis, and lipid metabolism. Key genes including ITSN1, NUP133, UPF3B, IFT88, and BIRC5 exhibited consistent network connectivity and distinct expression patterns across neuronal and glial cell populations. Enrichment analyses highlighted coordinated involvement of SUMOylation, mRNA processing, and axon guidance pathways. This study presents a reproducible, hypothesis-generating computational framework for prioritizing network-peripheral gene modules relevant to ASD. The findings support a distributed, systems-level model of ASD pathophysiology and identify candidate molecular modules for future experimental and translational investigation.</p>\u0000 </div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Value of lncRNA LINC00641 as a Potential Biomarker for Diagnosis of Alzheimer’s Disease and Elucidation of its Underlying Molecular Mechanism","authors":"Lihong Ren,&nbsp;Wenjun Zhang,&nbsp;Yumei Liu,&nbsp;Wuying Wang","doi":"10.1007/s12031-026-02484-2","DOIUrl":"10.1007/s12031-026-02484-2","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is a neurodegenerative disease with progressive cognitive impairment as the main clinical manifestation. Long non-coding RNAs (lncRNAs) are crucial regulators of diverse cellular processes. This study examined the clinical significance and underlying mechanisms of LINC00641 in AD diagnosis. qRT-PCR was used to measure plasma LINC00641 levels in AD patients, and its diagnostic value was assessed using ROC curve. Cell proliferation was measured via the CCK-8 assay. Apoptosis and AD-related proteins were detected by ELISA. The interaction between LINC00641 and its downstream target miR-501-3p was validated through online network prediction and dual-luciferase reporter assay. Plasma LINC00641 expression was lower in AD patients than in controls. It correlated positively with Aβ42 and negatively with p-Tau181 and p-Tau217. Combining of LINC00641 with clinical markers obviously improved diagnostic accuracy for distinguishing AD patients. Overexpression of LINC00641 restored the viability of H19-7 cells after Aβ42 treatment, and reduced levels of cleaved Caspase-3, Aβ42, p-Tau181/Tau, and p-Tau217/Tau. Functionally, miR-501-3p acts downstream of LINC00641. The cellular effects of LINC00641 overexpression were reversed by co-transfection with miR-501-3p mimic. Overexpression of LINC00641 downregulated miR-501-3p expression, restoring neuronal cell viability and reducing cell damage. Targeting LINC00641 holds potential as a diagnostic biomarker and therapeutic candidate for AD, which requires further validation in animal models.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the Gut-Brain-Ferroptosis Axis: Molecular Mechanisms and Therapeutic Potential in Alzheimer’s Disease and Epilepsy","authors":"Mohamed N. Fawzy,&nbsp;Mohamed K. Fathy","doi":"10.1007/s12031-026-02490-4","DOIUrl":"10.1007/s12031-026-02490-4","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) and epilepsy share underlying mechanisms of oxidative stress and neuroinflammation, yet effective targeted therapies remain limited. This review presents a novel integrative model linking gut microbiota dysbiosis to ferroptosis, an iron-dependent form of regulated cell death. We propose a vicious cycle in which dysbiosis promotes systemic inflammation and disrupts cerebral iron homeostasis, impairing the glutathione/GPX4 antioxidant system and sensitizing neurons to lipid peroxidation and ferroptotic death. This neuronal damage further fuels neuroinflammation and may exacerbate gut barrier dysfunction. Evidence from both conditions reveals altered gut microbiota alongside ferroptosis markers such as iron accumulation, reduced GPX4, and elevated lipid peroxides. Therapeutically, we examine two complementary approaches: central inhibition of ferroptosis using specific inhibitors and iron chelators, and peripheral modulation of the gut-brain axis via probiotics, prebiotics, or fecal transplantation. Preclinical studies indicate that targeting either pathway can reduce pathology and improve outcomes. We conclude that the most promising strategy involves combined therapies that simultaneously inhibit ferroptosis and restore gut microbial balance, offering a novel, multi-target approach to disrupt the pathogenic cycle in AD and epilepsy.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147336382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lower Plasma Serotonin is Associated with Higher Amyloid Burden, Hippocampal Atrophy, and Cognitive decline in Alzheimer’s Disease: A 24-Month Longitudinal Study","authors":"Yingbo Han,&nbsp;Li Liu,&nbsp;Li Chang,&nbsp;Xiaomin Ge,&nbsp;Qianqian Chen,&nbsp;Qian Li,&nbsp;Hehua Li,&nbsp;Wenchao Li,&nbsp;For the Alzheimer’s Disease Neuroimaging Initiative","doi":"10.1007/s12031-026-02497-x","DOIUrl":"10.1007/s12031-026-02497-x","url":null,"abstract":"<div><p>This study investigated longitudinal plasma serotonin dynamics across the Alzheimer’s disease (AD) continuum (cognitively normal [CN], mild cognitive impairment [MCI], and AD) to determine whether baseline serotonin and its 24-month change are associated with CSF amyloid-β (Aβ42), tau biomarkers, amyloid PET burden, structural brain integrity, and cognitive decline. Data from 959 ADNI participants (CN = 306, MCI = 421, AD = 232) with baseline and 24-month follow-up were analyzed. Measures included plasma serotonin, CSF biomarkers (Aβ42, total tau, p-tau181), florbetapir PET, MRI (hippocampal volume, cortical thickness), and cognitive tests (MMSE, ADAS-Cog 11, CDR-SB). Group differences were tested using ANOVA or Kruskal–Wallis, and associations were examined via partial correlations and mixed-effects models adjusted for age, sex, education, and APOE ε4, with FDR correction. The results revealed that baseline plasma serotonin levels showed a stepwise decline across the clinical continuum (CN &gt; MCI &gt; AD; <i>p</i> ≤ 0.05), consistent with progressive serotonergic dysregulation. In AD participants, higher baseline serotonin was significantly associated with less amyloid pathology and preserved brain structure, including higher CSF Aβ42 (β = 0.28, FDR <i>p</i> = 0.01), lower florbetapir PET SUVR (β = −0.31, FDR <i>p</i> = 0.02), and larger hippocampal volume (β = 0.33, FDR <i>p</i> = 0.02). Higher serotonin was also linked to better cognitive performance (MMSE: β = 0.22, FDR <i>p</i> = 0.02; ADAS-Cog 11: β = −0.24, FDR <i>p</i> = 0.02). Longitudinally, decreases in serotonin over 24 months in AD were associated with worsening amyloid burden (ΔPET SUVR: β = −0.29, FDR <i>p</i> = 0.02) and accelerated hippocampal atrophy (β = 0.32, FDR <i>p</i> = 0.01). Baseline serotonin predicted smaller 24-month declines in CSF Aβ42 (β = 0.28, FDR <i>p</i> = 0.01) and reduced hippocampal volume loss (β = 0.31, FDR <i>p</i> = 0.01). In CN and MCI groups, associations between serotonin and AD biomarkers or cognitive outcomes were not significant after FDR correction. On the whole, lower plasma serotonin levels are linked to amyloid pathology, hippocampal neurodegeneration, and cognitive decline in AD, supporting serotonin’s potential as a stage-specific biomarker and mechanistic contributor to disease progression. Integrative longitudinal studies are needed to clarify causality and evaluate serotonergic pathways as therapeutic targets.</p></div>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":"76 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}