Neurotherapeutics最新文献

{"title":"Pharmacological modulation with the LXR agonist T0901317 attenuates motor pathology in the SOD1G93A mouse model of ALS","authors":"Luis C. Fernández-Beltrán,&nbsp;Irene García-Toledo,&nbsp;Karen Javaloyes García,&nbsp;Irene Jiménez-Coca,&nbsp;Jesús Jiménez-Rodríguez,&nbsp;Anna Fernández-Bernal,&nbsp;Juan M. Godoy-Corchuelo,&nbsp;Manuel Portero-Otín,&nbsp;Silvia Corrochano","doi":"10.1016/j.neurot.2026.e01062","DOIUrl":"10.1016/j.neurot.2026.e01062","url":null,"abstract":"<div><div>Dysregulation of cholesterol metabolism and neuroinflammation are critical drivers of Amyotrophic Lateral Sclerosis (ALS) pathology. Liver X receptors (LXRs) are master regulators of cholesterol homeostasis and immune responses. Here, we evaluated the therapeutic potential of chronic pharmacological modulation using the potent synthetic agonist T0901317 (T0) in the hSOD1^G93A mouse model. To assess both long-term functional outcomes and the underlying molecular mechanisms, T0 was administered via two distinct experimental designs. In a longitudinal cohort treated from postnatal day 60 (P60) until the humane endpoint, T0-treated SOD1G93A mice exhibited delayed body weight loss and sustained improvements in neuromuscular strength and motor coordination. Critically, this continuous treatment preserved functional motor unit connectivity, delayed overall clinical progression, and significantly extended median lifespan. While protective in both sexes, the survival benefit was slightly more pronounced in females. Molecular characterization revealed that the early systemic T0 administration successfully engaged canonical LXR targets in the spinal cord, driving a significant transcriptional upregulation of cholesterol efflux pathways and suppressing pro-inflammatory signaling cascades. This response induced a lipid partitioning, evidenced by a significant accumulation of cholesterol esters within the central nervous system, potentially mitigating lipotoxicity. Taken together, these findings demonstrate that T0901317 treatment exerts a significant beneficial effect, highlighting the pharmacological modulation of these lipid and inflammatory networks as a promising therapeutic strategy for ALS.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 5","pages":"Article e01062"},"PeriodicalIF":7.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892245","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":"Corrigendum to ‘Nicotinamide riboside, pterostilbene and ibudilast protect motor neurons and extend survival in ALS mice’","authors":"Rafael Lo’pez-Blanch,&nbsp;Rosario Salvador-Palmer,&nbsp;María Oriol-Caballo,&nbsp;Paz Moreno-Murciano,&nbsp;Ryan W. Dellinger,&nbsp;Jos’e M. Estrela,&nbsp;Elena Obrador","doi":"10.1016/j.neurot.2026.e01070","DOIUrl":"10.1016/j.neurot.2026.e01070","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 5","pages":"Article e01070"},"PeriodicalIF":7.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892303","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":"Cardiometabolic disease is associated with distinct proteomic signatures of acute disease activity in multiple sclerosis","authors":"Darin T. Okuda,&nbsp;Katy W. Burgess,&nbsp;Crystal M. Wright,&nbsp;Morgan C. Jones-McCreary,&nbsp;Isabella J. Huddleston,&nbsp;Jose R. Santoyo,&nbsp;Tom G. Punnen,&nbsp;Peter V. Sguigna,&nbsp;Lauren M. Tardo,&nbsp;Christine Lebrun-Frénay,&nbsp;Olaf Stüve,&nbsp;Diem H. Tran,&nbsp;Tatum M. Moog","doi":"10.1016/j.neurot.2026.e01060","DOIUrl":"10.1016/j.neurot.2026.e01060","url":null,"abstract":"<div><div>Multiple sclerosis (MS) disease activity and treatment response may be influenced by systemic health factors, including cardiometabolic disease (CMD). This study evaluated how CMD influences inflammatory protein profiles and whether CMD modifies the effect of disease-modifying therapy (DMT). A retrospective study was conducted within a single academic MS center. All participants underwent commercial multi-analyte proteomic testing (Octave® Bioscience). CMD was defined as hypertension, type 2 diabetes mellitus, and/or dyslipidemia. Four groups were analyzed: untreated without CMD, untreated with CMD, DMT-treated without CMD, and DMT-treated with CMD. A multivariable variability index (MVI) was calculated across 18 age- and sex-adjusted proteins, and CMD burden (one, two, or three conditions) was assessed. A total of 287 MS individuals were included (84% White, 78% female). Among untreated individuals, those with CMD demonstrated significantly higher concentrations of proteins associated with acute MS disease activity, including MIP 3-alpha (CCL20) (p = 0.0078), CUB domain-containing protein 1 (CDCP1) (p = 0.0176), and TRAIL-R1 (TNFRSF10A) (p = 0.0002). In treated individuals, CMD was associated with higher levels of monokine induced by gamma interferon (CXCL9) (p = 0.0025), NfL (p = 0.0201), serpin family A member 9 (p = 0.0291), and TRAIL-R1 (p = 0.0002), as well as lower levels of protogenin (p = 0.0376). MVI values were elevated in both CMD groups. CMD was associated with higher odds of prior relapse and/or MRI activity within two years before proteomic testing (OR 5.48, 95% CI: [1.18–25.40], p = 0.0227). Protein concentrations increased with greater CMD burden. Clinically measurable proteins associated with acute MS disease activity are elevated in individuals with CMD and increase with comorbidity burden, in both DMT-treated and untreated groups.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 5","pages":"Article e01060"},"PeriodicalIF":7.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148930723","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":"Author response to Commentary on \"Long-term safety and efficacy of deoxycytidine/deoxythymidine in treatment of POLG-related disorders\"","authors":"Kenneth A. Myers,&nbsp;Daniela Buhas,&nbsp;Paula J. Waters","doi":"10.1016/j.neurot.2026.e01072","DOIUrl":"10.1016/j.neurot.2026.e01072","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 5","pages":"Article e01072"},"PeriodicalIF":7.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148930741","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":"Targeting SUV4–20H2-mediated H4K20 methylation restrains growth and migration in pediatric high-grade astrocytomas","authors":"Angeliki-Ioanna Giannopoulou,&nbsp;Elisavet Kosma,&nbsp;Dimitrios S. Kanakoglou,&nbsp;Alexia Klonou,&nbsp;Panagiotis Sarantis,&nbsp;Maria A. Papanikolaou,&nbsp;Andreas Mitsios,&nbsp;Spyros Sgouros,&nbsp;Penelope Korkolopoulou,&nbsp;Athanasios G. Papavassiliou,&nbsp;Christina Piperi","doi":"10.1016/j.neurot.2026.e01053","DOIUrl":"10.1016/j.neurot.2026.e01053","url":null,"abstract":"<div><div>Pediatric astrocytomas are characterized by increased molecular and clinical heterogeneity with epigenetic alterations contributing to aggressiveness and therapy resistance. The repressive histone mark H4K20 trimethylation (H4K20me3) and the methyltransferase SUV4–20H2 (KMT5C) are critical regulators of chromatin integrity and genome stability, with limited investigation in pediatric astrocytomas. KMT5C mRNA levels were evaluated in a publicly available pediatric gliomas database using bioinformatic analysis. Investigation of SUV4–20H2 and H4K20me3 expression was performed in a cohort of 43 pediatric astrocytoma tissues by immunohistochemistry. Their functional role and mechanism of action was investigated in pediatric glioma cell lines by using the substrate-competitive inhibitor of SUV4-20, A-196. Cell viability, apoptosis and migration were assessed using XTT, cleaved PARP, and wound healing assays, respectively. Effects of treatment on H4K20 methylation, DNA damage, mitotic stress [Polo-like kinase (PLK1) expression], and invasion markers (N-cadherin, β-catenin expression) were examined by western immunoblotting. KMT5C mRNA was significantly enriched in pediatric high-grade astrocytomas compared to low-grade tumors. A significant elevation of SUV4–20H2 and H4K20me3 expression was detected in astrocytoma tissues indicating epigenetic dysregulation contributing to malignancy. Treatment with A-196 reduced cell proliferation of pediatric glioma cell lines and induced apoptosis in a dose-dependent manner. It further impaired cell migration, accompanied by reduced N-cadherin and β-catenin expression. Mechanistically, inhibition of SUV4-20 depleted H4K20me3, inducing chromatin destabilization, replication-associated DNA damage and was associated with increased PLK1 expression, consistent with activation of a mitotic stress response. Our findings indicate that SUV4–20H2-mediated H4K20 activity in pediatric high-grade astrocytomas maintains their growth and migratory potential by regulating chromatin integrity and may serve as potential therapeutic target.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 5","pages":"Article e01053"},"PeriodicalIF":7.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840846","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":"Reduction in membrane AMPA receptor subunit 2 in left prefrontal cortex correlates with post-stroke depression","authors":"Yipeng Yu,&nbsp;Rong Fu,&nbsp;Haokun Rong,&nbsp;Qi Fang","doi":"10.1016/j.neurot.2026.e01063","DOIUrl":"10.1016/j.neurot.2026.e01063","url":null,"abstract":"<div><div>Post-stroke depression (PSD) is a prevalent and debilitating complication of stroke. While ischemic lesion in left prefrontal cortex (PFC) is a recognized risk factor, the underlying mechanisms linking this locus to PSD remain poorly defined. The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit 2 (GluA2) plays a critical role in neuroplasticity and mood regulation. In this study, a PSD rat model was used to investigate the pathophysiological mechanisms in left PFC through behavioral testing, biochemical assays, and pharmacological interventions targeting protein kinase C alpha (PKCα) and protein interacting with C kinase 1 (PICK1)-GluA2 binding. The results demonstrated that PSD reduced membrane GluA2 in left PFC. Mechanistically, PICK1 participated in the phosphorylation of GluA2 by PKCα, which in turn facilitated the reduction of membrane GluA2. Crucially, both inhibition of PKCα and disruption of PICK1-GluA2 binding rescued membrane GluA2 in left PFC without affecting total GluA2 expression and alleviated depressive-like behaviors of PSD rats. These findings suggest that reduced membrane GluA2 in left PFC correlates with PSD and may represent a potentially therapeutic target.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 5","pages":"Article e01063"},"PeriodicalIF":7.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920215","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":"Long-term safety and efficacy of deoxycytidine/deoxythymidine in treatment of POLG-related disorders","authors":"Anthony C.T. Cheung,&nbsp;Saoussen Berrahmoune,&nbsp;Christelle Dassi,&nbsp;Heather Pekeles,&nbsp;Tommy Gagnon,&nbsp;Paula J. Waters,&nbsp;Ralf Eberhard,&nbsp;Daniela Buhas,&nbsp;Kenneth A. Myers","doi":"10.1016/j.neurot.2026.e00945","DOIUrl":"10.1016/j.neurot.2026.e00945","url":null,"abstract":"<div><div>We evaluated the safety and efficacy of enteral deoxycytidine/deoxythymidine combination therapy in treatment of POLG-related disorders, genetic mitochondrial diseases characterized by progressive neurological degeneration. A single-centre open-label phase II trial was conducted. Inclusion criteria included: age 3 months to 60 years, clinical diagnosis of POLG-related disorder, and biallelic pathogenic <em>POLG</em> variants. Participants received deoxycytidine/deoxythymidine initially at 100 mg/kg/day (50 mg/kg deoxycytidine and 50 mg/kg deoxythymidine), titrated to 400 mg/kg/day over three weeks. The current protocol is a 60-month treatment period with primary outcomes the Newcastle Mitochondrial Disease Scale sections I-III and serum growth differentiation factor 15. Secondary outcomes include quality of life questionnaires, seizure diary, EEG, and blood and urine laboratory tests assessing end organ function. Outcomes were assessed at baseline, 1-month, 2-month, 3-month, and 6-month timepoints, then every 6 months thereafter. Twenty-five individuals (14 male, 11 female; mean age 12.3 years) started deoxycytidine/deoxythymidine. Five died during the trial and five withdrew. The most common treatment-related adverse event was diarrhea. Newcastle Mitochondrial Disease Scale sections I-III score decreased (improved) from baseline at all timepoints from 1 month to 24 months (p &lt; 0.05). Serum growth differentiation factor 15 significantly decreased (improved) from baseline at 1-month, 2-month, and 3-month timepoints (p &lt; 0.05). Quality of life score improved at 3-month, 12-month, and 18-month timepoints (p &lt; 0.05). In summary, our data suggest deoxycytidine/deoxythymidine is safe and effective for POLG-related disorders; however, further study is needed to clarify the therapeutic mechanism(s) so that the treatment can be refined and optimized.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e00945"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258995","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":"Efficacy and safety of dual antiplatelet treatment up to 72 hours after mild ischemic stroke or transient ischemic attack in patients with established cardiovascular disease","authors":"Zhang Xia,&nbsp;Ying Gao,&nbsp;Weiqi Chen,&nbsp;S. Claiborne Johnston,&nbsp;Pierre Amarenco,&nbsp;Philip M. Bath,&nbsp;Xuan Wang,&nbsp;Peiyuan Gao,&nbsp;Hongyi Yan,&nbsp;Tingting Wang,&nbsp;Yingying Yang,&nbsp;Yanli Zhang,&nbsp;Yongjun Wang,&nbsp;Yilong Wang,&nbsp;Yuesong Pan","doi":"10.1016/j.neurot.2026.e00963","DOIUrl":"10.1016/j.neurot.2026.e00963","url":null,"abstract":"<div><div>Patients with established cardiovascular disease (CVD) may have a higher risk of recurrent stroke and a higher prevalence of antiplatelet resistance than those without CVD. This study investigated the efficacy and safety of dual antiplatelet therapy (DAPT) with clopidogrel plus aspirin in patients with established CVD. This is a secondary post hoc analysis of the Intensive Statin and Antiplatelet Therapy for Acute High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial. Patients with mild ischemic stroke (IS) or high-risk transient ischemic attack (TIA) of presumed atherosclerotic cause were randomized to receive either DAPT or aspirin alone within 72 h after symptom onset. Established CVD was defined as a prior diagnosis of IS, coronary artery disease, TIA, or peripheral arterial disease. The primary efficacy and safety outcomes were the occurrence of new stroke and moderate-to-severe bleeding within 90 days. This study included 6100 patients, with a mean age of 63.7 ± 9.6 years and 35.8% of female. DAPT was associated with a reduced risk of new stroke (hazard ratio [HR] = 0.67, 95%CI: 0.54–0.85, <em>P</em> &lt; 0.001) in non-CVD patients but not in those with established CVD (HR = 0.97, 95%CI: 0.73–1.28, <em>P</em> = 0.82), compared with aspirin (<em>P</em> for interaction = 0.04). Moderate-to-severe bleeding did not differ by antiplatelet treatments across CVD subgroups (<em>P</em> for interaction = 0.32). In the INSPIRES trial, patients with established CVD may benefit less from clopidogrel–aspirin in reducing the risk of recurrent stroke within 90 days than those without CVD after mild IS or high-risk TIA.</div></div><div><h3>Trial registration</h3><div>URL: <span><span>https://www.clinicaltrials.gov</span><svg><path></path></svg></span>; Unique identifier: NCT03635749.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e00963"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422804","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":"Deep brain stimulation in pediatric drug-resistant epilepsy: Implications for the developing connectome","authors":"Karim Mithani,&nbsp;Thiemo F. Dinger,&nbsp;Carolina Gorodetsky,&nbsp;George M. Ibrahim","doi":"10.1016/j.neurot.2026.e00968","DOIUrl":"10.1016/j.neurot.2026.e00968","url":null,"abstract":"<div><div>Epilepsy is increasingly recognized as a disorder of brain networks, and intracranial neuromodulation has emerged as a therapeutic strategy for individuals with drug-resistant epilepsy (DRE). In pediatric populations, however, ongoing brain development raises important questions regarding safety, efficacy, and long-term consequences of chronic neuromodulation. In this review, we examine the emerging role of deep brain stimulation (DBS) in the treatment of DRE in children and adolescents. We synthesize current evidence supporting the neurobiological rationale for DBS in pediatric epilepsy, with particular attention to thalamic and limbic targets and their associated networks. Available clinical data are critically reviewed, including findings from emerging prospective studies, with emphasis on seizure outcomes, quality of life, neurodevelopmental trajectories, and safety. We also discuss surgical, clinical, and ethical considerations unique to the application of chronic intracranial stimulation in the developing brain. Finally, we outline future directions for the field, including network-informed target selection, comparisons to responsive stimulation paradigms, and the need for developmentally relevant, longitudinal outcome measures. Although pediatric DBS remains largely off-label and supported by limited high-quality evidence, it is increasingly incorporated into specialized epilepsy care. Continued progress will depend on coordinated multicenter efforts that prioritize both seizure control and long-term neurodevelopmental and psychosocial outcomes.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e00968"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471978","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":"Nervonic acid supplementation mitigates disease severity biomarkers in adrenoleukodystrophy","authors":"Chenxu Li,&nbsp;Kai Braaten,&nbsp;Ann B. Moser,&nbsp;Wedad Fallatah,&nbsp;Maggie Lorentson,&nbsp;Suzette Huguenin,&nbsp;Anna Torrey,&nbsp;Marcia R. Terluk,&nbsp;Willa Durose,&nbsp;Erin Nolan,&nbsp;Christopher Staley,&nbsp;Subbaya Subramanian,&nbsp;Troy C. Lund,&nbsp;Reena V. Kartha","doi":"10.1016/j.neurot.2026.e00890","DOIUrl":"10.1016/j.neurot.2026.e00890","url":null,"abstract":"<div><div>X-linked adrenoleukodystrophy (ALD) is a severe neurometabolic disorder caused by mutations in the <em>ABCD1</em> gene, leading to impaired peroxisomal β-oxidation of very long-chain fatty acids (VLCFAs). The accumulation of saturated VLCFAs, predominantly C26:0, in plasma and across all tissues, contributes to adrenal dysfunction and progressive neurodegeneration. No approved therapy addresses the diverse spectrum of ALD manifestations, underscoring the urgent need for safe, accessible, and preventive treatments. Nervonic acid (NA), a monounsaturated fatty acid, is potentially beneficial for ALD through its neuroprotective effects. Here, we report the safety and therapeutic efficacy of NA in a 4-week dietary intervention study using a mouse model of ALD. NA treatment significantly decreased plasma C26:0-lysophosphatidylcholine, a diagnostic and disease-severity biomarker of ALD, by about 60% as early as one week after intervention. After 4-week treatment, NA markedly reduced free C26:0 and total saturated VLCFA levels in plasma and tissues. Moreover, we observed approximately 56% reduction in brain C26:0-lysophosphatidylcholine levels in NA-fed mice, an effect not reported with other drug intervention. Through comparative microbiome analysis, we show for the first time distinct baseline differences between ALD and wild-type mice, with dietary fatty acid supplementation preventing further dysbiosis. No adverse effects on body weight or food intake were observed throughout the study. Overall, this is the first report demonstrating that an oral dietary fatty acid can ameliorate the hallmark biochemical abnormalities of ALD in plasma and brain, highlighting its potential as a safe and effective therapy, particularly for presymptomatic individuals carrying this genetic defect.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 4","pages":"Article e00890"},"PeriodicalIF":7.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639473","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}