Metabolic brain disease最新文献

{"title":"CRISPR-Enabled functional genomics in hPSCs-derived neural models for autism spectrum disorder.","authors":"S T Gopukumar, Madhumita Saha, Tanveen Kaur Soni, Eid Semer Alatwi, Gazala Afreen Khan, Mohammad Rehan Asad, Samer Shamshad, Sunil Tadakod, Alok Sharma, Uddalak Das","doi":"10.1007/s11011-026-01968-9","DOIUrl":"10.1007/s11011-026-01968-9","url":null,"abstract":"<p><p>Autism Spectrum Disorder (ASD) is a genetically heterogeneous neurodevelopmental condition in which hundreds of individually rare risk variants converge on a small number of shared biological pathways, including synaptic scaffolding, chromatin remodeling, excitation-inhibition balance, and cellular energy metabolism. Translating this genetic heterogeneity into mechanistic insight requires experimental systems capable of interrogating individual gene functions in human-relevant neural contexts at scale. CRISPR-enabled functional genomics in human pluripotent stem cell (hPSC)-derived neural models, spanning neural progenitors, cortical and inhibitory neurons, astrocytes, microglia, and brain organoids, provides precisely this capability. By integrating pooled perturbation screens with multimodal readouts including single-cell and spatial transcriptomics, chromatin accessibility profiling, proximity labeling proteomics, multi-electrode array electrophysiology, and metabolic flux analysis, these platforms enable systematic, causal mapping of ASD gene function at system resolution. Early applications have already revealed convergent mechanisms: BAF complex disruption expands the ventral progenitor pool and biases its fate toward oligodendrocyte and interneuron lineages; ADNP loss impairs microglial synaptic pruning through altered endocytic trafficking; and mTOR pathway dysregulation in PTEN- and TSC2-perturbed models links genetic risk directly to metabolic and mitochondrial dysfunction. Computational frameworks including MIMOSCA and SCEPTRE enable causal network reconstruction and pseudotime inference from these datasets, moving the field from gene lists toward pathway-level models of ASD pathobiology. Translational applications leverage isogenic iPSC panels and variant-level base and prime editing to stratify ASD variants by functional impact, informing gene therapy design for haploinsufficient targets such as CHD8 and SCN2A via AAV or antisense oligonucleotide delivery. Remaining challenges, including model developmental immaturity, batch variability, and the difficulty of modeling polygenic risk, are addressed by a roadmap integrating spatial perturbomics, AI-driven causal inference, and population-scale standardized biobanks. This review synthesizes the current state of CRISPR-based functional genomics in human stem cell neural models as a coherent experimental framework for converting ASD genetic associations into mechanistic understanding and therapeutic opportunity.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Significance of NAD anabolism profiles in neurological diseases.","authors":"Abhishek Kumar Mishra, Dipak Kumar, Sakshi Jaiswal, Nitin Mishra, Syed Ibrahim Rizvi","doi":"10.1007/s11011-026-01988-5","DOIUrl":"10.1007/s11011-026-01988-5","url":null,"abstract":"<p><p>Neurons are post-mitotic polarized cells with a higher energy budget which is required to maintain ion gradients, axonal trafficking, firing, and synaptic transmission. The increased cell surface area resulting from the extension of the neuronal membrane and the protrusion of axoplasm from the soma also significantly amplifies neuronal energy demands. To achieve bioenergetic homeostasis, neurons have a higher metabolic rate and engage in continuous NAD production. Biosynthesis of NAD occurs via the enzymatic conversion of tryptophan, and breakdown in NAD biosynthesis leads to neuronal deterioration and the accumulation of tryptophan metabolites in affected brain regions. There exists a good body of evidence linking associations between several neurological disorders and tryptophan metabolites, aberrant expression of NAD biosynthesis enzymes, and polymorphisms in genes encoding enzymes. This review describes the involvement of NAD biosynthetic enzymes in neuropathogenesis and disease. Further, it discusses the association of CNS disorders with various polymorphisms and altered levels of tryptophan metabolites in biofluids, as well as the prognostic value of NAD-associated biomolecules in neurological diseases. Together, the review suggests that quantifying tryptophan-catabolizing enzymes and tryptophan catabolites involved in NAD biosynthesis in biofluids provides a minimally invasive means to monitor neurodegenerative and neuropsychiatric processes. This approach offers a prognostic insight into disease progression, treatment efficacy, and individualized risk assessment.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AMPK activation by Aldometanib from Bigujing improves metabolic and cognitive dysfunction in aging mice.","authors":"Xiaoyu Wang, Shengyao Zhang, Qiongfang Wang, Jiajie Leng, Meng Zhang, Guoran Wan, Yi Zhu, Boyue Huang, Jianhua Ran","doi":"10.1007/s11011-026-01985-8","DOIUrl":"10.1007/s11011-026-01985-8","url":null,"abstract":"<p><p>Aging-related cognitive decline is closely associated with disrupted energy metabolism and impaired autophagic clearance in the brain. Aldometanib, an active ingredient from the traditional formulation Bigujing, exerts systemic metabolic benefits, but its effects on brain aging and the underlying mechanisms remain unclear. This study aims to evaluate the efficacy of Aldometanib in mitigating cognitive decline in D-galactose-induced aging mice, and to elucidate its potential mechanisms involving AMPK-mediated energy metabolism and autophagy regulation. Male C57BL/6 J mice were treated with D-gal for 42 days, with or without 100 μg/mL Aldometanib in drinking water. Cognitive function was evaluated using the novel object recognition test, Y-maze test, and the Morris water maze test. Brain tissues were analyzed for neuronal morphology, the total antioxidant capacity (T-AOC) and the expressions of senescence, AMPK/ACC pathway and autophagy-related proteins (p-mTOR, LC3B-II, P62). In vitro assays validated Aldometanib's mechanistic effects in D-gal-treated C8-D1A astrocytes and Neuro-2a cells. Aldometanib significantly mitigated D-gal-induced weight loss and cognitive deficits and alleviated neuronal atrophy and loss in the hippocampus and cortex. Aldometanib downregulated the expression of senescence markers P53, P21 and P16 and increased T-AOC levels. Mechanistically, Aldometanib specifically activated the AMPK/ACC pathway in neurons and astrocytes, suppressed mTOR phosphorylation and P62 accumulation, and enhanced autophagy both in vivo and in vitro. Aldometanib can effectively ameliorate the cognitive and physiological decline in aged mice by activating AMPK, suppressing mTOR and promoting autophagy, and enhancing antioxidant capacity. It represents a promising therapeutic candidate for age-related neurodegenerative diseases.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urinary metabolomics data and cognitive performance in an adult population.","authors":"Annika Kneipp, Inge Kirchberger, Dennis Freuer, Christine Meisinger, Jakob Linseisen","doi":"10.1007/s11011-026-01977-8","DOIUrl":"10.1007/s11011-026-01977-8","url":null,"abstract":"<p><p>With an ageing population, the social and economic burden of cognitive decline is increasing. Urinary metabolomics may offer a promising approach for identifying metabolic markers for early cognitive impairment and gaining insights into underlying biological mechanisms. The aim of this study was to investigate the association between urinary metabolites and cognitive performance in a population-based sample. Cognitive performance was assessed in 560 (digit span) and 553 participants (semantic verbal fluency) of the Metabolism, Nutrition and Immune System in Augsburg (MEIA) study. Urinary concentrations of 51 metabolites were quantified via ¹H nuclear magnetic resonance and normalized to creatinine (Nightingale Health, Finland). Overall and sex-specific associations between metabolites and cognitive outcomes were examined using multivariable linear regression models adjusted for demographic, lifestyle, and health-related confounders. Five metabolites were significantly associated with digit span performance: 3-hydroxyhippurate, trans-aconitate, and uracil in the overall sample, and taurine and pyroglutamate in men only. Eight metabolites were associated with verbal fluency, six of which were observed in the full cohort, namely, acetate, citrate, hippurate, pyroglutamate, taurine, and xanthosine, while glutamine showed associations exclusively in men and propylene glycol exclusively in women. After adjustment for multiple testing, none of the associations remained significant. Urinary metabolites related to energy, microbial, amino acid, and nucleotide metabolism showed domain- and sex-specific associations with cognitive performance. These exploratory findings point towards a potential involvement of systemic metabolic processes related to mitochondrial energy production, oxidative stress, inflammation, and neurotransmission, during early cognitive changes in the general population.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13570828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms of blood-brain barrier dysfunction caused by obesity: pathophysiological understandings and treatment targets.","authors":"Roshvin Kailashnath Pillai, Vinibha Rajakumari Illankovan, Rishvini Kailashnath Pillai, Mukesh Kumar, Srikanth Shastry, Alabsi Am, Srikanth Jeyabalan, Chetan Ashok, Vipin Kumar, Thakur Gurjeet Singh, Saminathan Kayarohanam, Chitra V, Vetriselvan Subramaniyan","doi":"10.1007/s11011-026-01986-7","DOIUrl":"10.1007/s11011-026-01986-7","url":null,"abstract":"<p><p>Chronic low-grade inflammation and systemic metabolic dysregulation are linked to obesity, a rapidly expanding worldwide health concern that affects the central nervous system (CNS) in addition to peripheral organs. Dysfunction of the blood-brain barrier (BBB), which impairs selective permeability, tight junction integrity, and neurovascular coupling, is one of its most serious neurobiological effects. The BBB, which is made up of pericytes, endothelial cells, and astrocytic end-feet, depends on specialized transporters and tight junction proteins like occludin, ZO-1, and claudin-5 to control the exchange of nutrients and xenobiotics. Pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and toll-like receptor 4 (TLR4) signaling cause obesity-induced meta-inflammation, which in turn causes endothelial NF-κB activation, leukocyte infiltration, and tight junction breakdown. BBB leakiness is simultaneously increased by intrinsic endothelial stress resulting from oxidative damage, mitochondrial dysfunction, defective autophagy, AMPK inhibition, and NAD⁺ depletion. LXR, PPAR, and ApoE signaling drive dysregulated lipid metabolism, which further impairs activity-dependent cerebral blood flow by interfering with neurovascular coupling and endothelial-astrocyte communication. By lowering inflammation, increasing tight junction expression, and boosting metabolic resilience, therapeutic interventions that target these molecular pathways, such as GLP-1 receptor agonists, PPAR-γ modulators, metformin, and statins, show promise in restoring the integrity of the BBB. Endothelial function is further reinforced, neuroinflammation is reduced, and BBB stability is supported by complementary lifestyle and dietary modifications such as regular exercise and nutrient-rich meals. The development of focused pharmaceutical and lifestyle approaches to prevent or correct neurovascular damage and concomitant cognitive decline is made possible by an understanding of the complex molecular pathways underlying obesity-related BBB dysfunction.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dihydromyricetin ameliorates cognitive dysfunction in SAMP8 mice via autophagy-mediated degradation of the NLRP3 inflammasome.","authors":"Xing-Ran Liu, Meng Zhang, Dan-Dan Chen, Jing-Ru Chang, Xian-Juan Kou","doi":"10.1007/s11011-026-01982-x","DOIUrl":"10.1007/s11011-026-01982-x","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is characterized by progressive cognitive decline and neuropathology, but its mechanisms remain incompletely understood. Impaired autophagy and overactivation of the NLRP3 inflammasome are thought to contribute to AD progression. Dihydromyricetin (DHM) is a natural flavonoid with known neuroprotective effects, yet it remains unclear whether DHM modulates the autophagy-lysosome pathway to suppress NLRP3 inflammasome activation and improve cognitive deficits. Here, we combined bioinformatics predictions with in vitro and in vivo experiments to investigate DHM's effects on autophagy and NLRP3 inflammasome signaling. Bioinformatic analysis of aging, AD, and cognition-related gene sets identified autophagy and immune regulation as key enriched pathways. Molecular docking predicted that DHM binds favorably to core autophagy and inflammasome proteins. In vitro, DHM (6.25-25 µg/mL) increased autophagy in BV2 microglia, as evidenced by an increased LC3-II/LC3-I ratio and ULK1 expression and reduced p62 accumulation, and markedly reduced LPS/ATP-induced upregulation of NLRP3, cleaved caspase-1, IL-1β, and IL-18. DHM also reduced LPS-induced intracellular ROS accumulation in BV2 cells and attenuated NF-κB p65 phosphorylation in SAMP8 hippocampus. In vivo, 8-week oral administration of DHM to senescence-accelerated mouse-prone 8 (SAMP8) mice, an accelerated aging model with AD-like cognitive and pathological features, enhanced hippocampal autophagy marker expression, reduced NLRP3 inflammasome-related proteins and AD-related pathological protein changes. Immunofluorescence and Western blot analyses showed that DHM increased the spatial association of NLRP3 with LC3- and LAMP1-positive structures, reduced ASC expression, and increased the lysosomal protease Cathepsin D. These molecular changes corresponded with improved spatial learning and memory in the Morris water maze. However, co-treatment with the autophagy inhibitor chloroquine (CQ) abolished the DHM's effects on autophagy markers, reversed its reduction of NLRP3-related inflammatory proteins, and negated its cognitive benefits. Taken together, these results suggest that DHM enhances autophagy-lysosome pathway activity and facilitates autophagy-associated suppression of NLRP3 inflammasome activation, thereby mitigating neuroinflammation and cognitive impairment in SAMP8 mice. This autophagy-dependent mechanism suggests that DHM, a well-tolerated natural compound, has potential as a multitarget therapeutic candidate for AD-like cognitive impairment.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential metabolic and cellular brain regional susceptibility in adult rats with chronic liver disease.","authors":"Dunja Simicic, Katarzyna Pierzchala, Olivier Braissant, Dario Sessa, Valérie McLin, Cristina Cudalbu","doi":"10.1007/s11011-026-01954-1","DOIUrl":"10.1007/s11011-026-01954-1","url":null,"abstract":"<p><p>Patients with type C hepatic encephalopathy (HE) present diverse symptoms, indicating disease-associated effects in multiple brain regions. While identifying the distinct metabolic and cellular changes in these regions could help explain the clinical variability of HE, this remains challenging. By leveraging the non-invasive capabilities of in-vivo ¹H-MR Spectroscopy (9.4T) and complementary ex-vivo histological assessments, we analyzed, longitudinal neurometabolic and morphological changes in the hippocampus, striatum, and cerebellum during the progression of chronic liver disease, induced type C HE in the bile duct ligated rat model (n = 41). We showed that while brain regions share common metabolic and cellular responses such as acute glutamine increase, glial activation, and neuronal alterations, they also display unique characteristics. The most striking difference was in the cerebellum, where the highest glutamine load (+ 134%) was associated with elevated lactate and reduced Purkinje soma surface, while the striatum showed the strongest osmolyte decrease despite having the lowest glutamine increase among the studied regions. Based on the early rise of glutamine across regions, we highlight glutamine as one of the molecular drivers of a cascade of metabolic and cellular abnormalities, together with ¹H-MRS as a valuable modality to investigate region-specific brain alterations in HE both in animal models and humans.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13569521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148945317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective impact of nicotinamide riboside and metformin on the hippocampus of male rats with diet-induced obesity.","authors":"Zahra Nasiri, Hora Amoozegar, Asma Sobhani, Mohammad Saeedi, Zahra Hosseinpour, Bahareh Hassanzadeh, Mohammadreza Aghabali, Mobin Alinia, Meysam Rahimipour, Mohammad Hojjati Far, Mehrangiz Ghafari, Elham Nadimi","doi":"10.1007/s11011-026-01966-x","DOIUrl":"10.1007/s11011-026-01966-x","url":null,"abstract":"<p><strong>Background: </strong>Obesity-induced metabolic disturbances are increasingly recognized as major contributors to hippocampal dysfunction and neurodegeneration. Chronic exposure to a high-fat diet (HFD) has been associated with hippocampal structural alterations, dysregulation of neurotrophic and metabolic signalling, and increased neuronal vulnerability, ultimately impairing cognitive performance.</p><p><strong>Objective: </strong>This study investigated the neuroprotective effects of nicotinamide riboside (NR), metformin (MET), and their combination on hippocampal structure, gene expression, and spatial memory in a male rat model of diet-induced obesity.</p><p><strong>Methods: </strong>Male Wistar rats were assigned to a lean control group or a high-fat diet (HFD) group and maintained on their respective diets for 10 weeks. During the final 4 weeks of the HFD protocol, HFD-fed rats received nicotinamide riboside (NR; 300 mg/kg/day), metformin (MET; 200 mg/kg/day), or their combination by oral gavage while continuing HFD feeding. Stereological analysis was performed to assess hippocampal subregion volumes (CA1 and dentate gyrus), neuronal survival, and total glial cell counts based on morphological criteria. Gene expression levels of Bdnf, Sirt1, Ppargc1a, Bax, Bcl-2, and Casp3 were measured using quantitative real-time PCR (qRT-PCR). Spatial learning and memory were evaluated using the Morris Water Maze (MWM) test.</p><p><strong>Results: </strong>HFD feeding induced obesity accompanied by hippocampal atrophy, altered expression of neurotrophic, metabolic, and apoptosis-related genes, and impaired spatial memory. Treatment with NR and MET, particularly in combination, was associated with attenuation of these alterations. The combination treatment showed the greatest improvement in hippocampal volume, greater neuronal preservation, reduced morphologically identified glial cell counts, and partial normalization of gene expression patterns. Behavioral analysis also indicated better performance in spatial learning and memory, with the NR + MET group showing the most pronounced improvement in escape latency and time spent in the target quadrant.</p><p><strong>Conclusion: </strong>NR and metformin were associated with beneficial effects on obesity-related hippocampal alterations, accompanied by favourable changes in apoptosis-related, metabolic, and neurotrophic gene expression as well as improved stereological indices of hippocampal integrity. The combined treatment generally produced greater improvements than either monotherapy. These findings support further investigation of NR and metformin as potential interventions for obesity-associated hippocampal dysfunction and cognitive impairment.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148945299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate as a metabolic-epigenetic hub in neurological disorders.","authors":"Yu Gu, Potao Zhang, Chunyan Lei","doi":"10.1007/s11011-026-01984-9","DOIUrl":"10.1007/s11011-026-01984-9","url":null,"abstract":"<p><p>Lactate, once considered merely a metabolic waste product of glycolysis, has emerged as a pivotal signaling molecule that bridges cellular metabolism and epigenetic regulation in the central nervous system. The discovery of protein lactylation in 2019 revealed a novel post-translational modification that directly linked lactate accumulation to changes in gene expression, fundamentally reshaping our understanding of how metabolic states influenced neural function and dysfunction. This comprehensive review synthesizes recent advances in lactate biology, encompassing the expanding enzymatic landscape of lactylation-including newly identified writers, erasers, and readers-and their roles in neurodegenerative diseases. We critically re-examine metabolic coupling models beyond the classical astrocyte-neuron lactate shuttle (ANLS), incorporating neuronal glycolytic capacity, oligodendrocyte-specific relay mechanisms, and cell type-specific monocarboxylate transporter (MCT) expression patterns. Furthermore, we explore the concentration-dependent duality of lactate effects through G protein-coupled receptor 81 (GPR81)/hydroxycarboxylic acid receptor 1 (HCAR1) signaling, the functional significance of non-histone lactylation in neural cells, and the interplay between lactylation and mitochondrial quality control, ferroptosis, and adult hippocampal neurogenesis. Finally, we discuss emerging therapeutic strategies targeting lactate metabolism and lactylation modifications -ranging from lactate dehydrogenase (LDH) inhibitors and MCT modulators to exercise-induced neuroprotection-and identify critical challenges for clinical translation. By integrating these cutting-edge findings, we provide an updated theoretical framework that positions lactate as a central node connecting metabolic reprogramming with epigenetic dysregulation in neurodegeneration.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148930568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain-derived neurotrophic factor via TRPM2 inhibition reduces amyloid-beta-mediated increases of apoptosis and mitochondrial oxidative neurotoxicity in neuronal cells.","authors":"Arif Demirdaş, Mustafa Nazıroğlu","doi":"10.1007/s11011-026-01980-z","DOIUrl":"10.1007/s11011-026-01980-z","url":null,"abstract":"<p><p>Brain-derived neurotrophic factor (BDNF) has particular importance in the modulation of Alzheimer's disease (AD)-related pathologies such as apoptosis and mitochondrial reactive oxygen species (mROS). The cation channel, transient receptor potential melastatin 2 (TRPM2), stimulation is important for the generation of AD-related pathologies. Antioxidant treatments through the inhibition of TRPM2 play an essential role in the inhibition of Ca²⁺ entry, mROS, and apoptosis changes in the SH-SY5Y neuronal cells. However, the effects of antioxidant and antiapoptotic roles of BDNF have not yet been studied in SH-SY5Y treated with amyloid-beta (Aβ). The aim of the present study was to investigate the protective action of BDNF via TRPM2 inhibition on the apoptotic and oxidant values in Aβ-induced SH-SY5Y cells. Five groups of SH-SY5Y cells were established: control, BDNF, Aβ, Aβ + BDNF, and Aβ + TRPM2 channel blockers. The Aβ-induced increases in intracellular Ca²⁺ and TRPM2 currents were decreased by BDNF and PARP-1 inhibition. The levels of mROS, intracellular ROS, dysfunction of mitochondrial membrane, SH-SY5Y death, apoptosis, and caspases (caspases-3, -8, and - 9) were increased in the cells treated with Aβ, although glutathione (GSH) and glutathione peroxidase (GSH-Px) were decreased by the treatment. However, the levels of these oxidative and apoptotic markers through the increases in GSH and GSH-Px were reduced in the cells by the incubations of BDNF and TRPM2 channel blockers. Finally, it was shown that BDNF protects neuronal cells against Aβ-induced excessive Ca²⁺ entry, oxidative stress, and apoptotic parameters via inhibiting TRPM2. Treatment with BDNF appears to have the capacity to reduce apoptosis and oxidative stress caused by Aβ through inhibiting TRPM2.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148930517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}