{"title":"Structural insights into the diverse actions of magnesium on NMDA receptors.","authors":"Xuejing Huang, Xiaole Sun, Qinrui Wang, Jilin Zhang, Han Wen, Wan-Jin Chen, Shujia Zhu","doi":"10.1016/j.neuron.2025.01.021","DOIUrl":"10.1016/j.neuron.2025.01.021","url":null,"abstract":"<p><p>Magnesium (Mg<sup>2+</sup>) is a key regulatory ion of N-methyl-ᴅ-aspartate (NMDA) receptors, including conferring them to function as coincidence detectors for excitatory synaptic transmission. However, the structural basis underlying the Mg<sup>2+</sup> action on NMDA receptors remains unclear. Here, we report the cryo-EM structures of GluN1-N2B receptors and identify three distinct Mg<sup>2+</sup>-binding pockets. Specifically, site Ⅰ is located at the selectivity filter where an asparagine ring forms coordination bonds with Mg<sup>2+</sup> and is responsible for the voltage-dependent block. Sites Ⅱ and Ⅲ are located at the N-terminal domain (NTD) of the GluN2B subunit and involved in the allosteric potentiation and inhibition, respectively. Site Ⅱ consists of three acidic residues, and the combination of three mutations abolishes the GluN2B-specific Mg<sup>2+</sup> potentiation, while site Ⅲ overlaps with the Zn<sup>2+</sup> pocket, and mutations here significantly reduce the inhibition. Our study enhances the understanding of multifaceted roles of Mg<sup>2+</sup> in NMDA receptors and synaptic plasticity.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"1006-1018.e4"},"PeriodicalIF":14.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuronPub Date : 2025-04-02Epub Date: 2025-03-12DOI: 10.1016/j.neuron.2025.02.007
Rocio Vicario, Stamatina Fragkogianni, Maria Pokrovskii, Carina Meyer, Estibaliz Lopez-Rodrigo, Yang Hu, Masato Ogishi, Araitz Alberdi, Ann Baako, Oyku Ay, Isabelle Plu, Véronique Sazdovitch, Sebastien Heritier, Fleur Cohen-Aubart, Natalia Shor, Makoto Miyara, Florence Nguyen-Khac, Agnes Viale, Ahmed Idbaih, Zahir Amoura, Marc K Rosenblum, Haochen Zhang, Elias-Ramzey Karnoub, Palash Sashittal, Akhil Jakatdar, Christine A Iacobuzio-Donahue, Omar Abdel-Wahab, Viviane Tabar, Nicholas D Socci, Olivier Elemento, Eli L Diamond, Bertrand Boisson, Jean-Laurent Casanova, Danielle Seilhean, Julien Haroche, Jean Donadieu, Frederic Geissmann
{"title":"Role of clonal inflammatory microglia in histiocytosis-associated neurodegeneration.","authors":"Rocio Vicario, Stamatina Fragkogianni, Maria Pokrovskii, Carina Meyer, Estibaliz Lopez-Rodrigo, Yang Hu, Masato Ogishi, Araitz Alberdi, Ann Baako, Oyku Ay, Isabelle Plu, Véronique Sazdovitch, Sebastien Heritier, Fleur Cohen-Aubart, Natalia Shor, Makoto Miyara, Florence Nguyen-Khac, Agnes Viale, Ahmed Idbaih, Zahir Amoura, Marc K Rosenblum, Haochen Zhang, Elias-Ramzey Karnoub, Palash Sashittal, Akhil Jakatdar, Christine A Iacobuzio-Donahue, Omar Abdel-Wahab, Viviane Tabar, Nicholas D Socci, Olivier Elemento, Eli L Diamond, Bertrand Boisson, Jean-Laurent Casanova, Danielle Seilhean, Julien Haroche, Jean Donadieu, Frederic Geissmann","doi":"10.1016/j.neuron.2025.02.007","DOIUrl":"10.1016/j.neuron.2025.02.007","url":null,"abstract":"<p><p>Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders associated with mitogen-activated protein (MAP)-kinase-activating mutations and an increased risk of neurodegeneration. We found microglial mutant clones in LCH and ECD patients, whether or not they presented with clinical symptoms of neurodegeneration, associated with microgliosis, astrocytosis, and neuronal loss, predominantly in the rhombencephalon gray nuclei. Neurological symptoms were associated with PU.1<sup>+</sup> clone size (p = 0.0003) in patients with the longest evolution of the disease, indicating a phase of subclinical incipient neurodegeneration. Genetic barcoding analysis suggests that clones may originate from definitive or yolk sac hematopoiesis, depending on the patients. In a mouse model, disease topography was attributable to a local clonal proliferative advantage, and microglia depletion by a CSF1R-inhibitor limited neuronal loss and improved survival. These studies characterize a neurodegenerative disease associated with clonal proliferation of inflammatory microglia. The long preclinical stage represents a therapeutic window before irreversible neuronal depletion.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"1065-1081.e13"},"PeriodicalIF":14.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Dietary availability acutely influences puberty onset via a hypothalamic neural circuit.","authors":"Teppei Goto, Mitsue Hagihara, Satsuki Irie, Takaya Abe, Hiroshi Kiyonari, Kazunari Miyamichi","doi":"10.1016/j.neuron.2025.01.015","DOIUrl":"10.1016/j.neuron.2025.01.015","url":null,"abstract":"<p><p>Reproduction poses a substantial burden, especially for mammalian females. Puberty onset serves as a vital checkpoint, regulated based on the body's energy state, to prevent inappropriate reproductive activity under malnutrition. However, the neural basis of this puberty checkpoint remains poorly understood. Here, we demonstrate that peripubertal malnutrition in female mice reduces the synchronous activity episodes of arcuate kisspeptin neurons, which are critical regulators of the gonadotropin axis. Improved dietary availability increased the frequency of this pulsatile activity, facilitating puberty onset. Using a viral-genetic approach, we show that the activity of agouti-related protein neurons in the arcuate nucleus, a hunger center, can bidirectionally regulate the pulsatile activity of kisspeptin neurons and follicular maturation in the ovaries. Collectively, a neural circuit connecting feeding to reproductive centers acts as an adjuster of the frequency of pulsatile kisspeptin neuron activity based on dietary availability, contributing to the neural basis of the puberty checkpoint.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"1036-1050.e5"},"PeriodicalIF":14.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"BACE1-dependent cleavage of GABA<sub>A</sub> receptor contributes to neural hyperexcitability and disease progression in Alzheimer's disease.","authors":"Danlei Bi, Hong Bao, Xiaoli Yang, Zujun Wu, Xiaoxu Yang, Guangwei Xu, Xiaoming Liu, Zhikun Wan, Jiachen Liu, Junju He, Lang Wen, Yuying Jing, Ruijie Zhu, Zhenyu Long, Yating Rong, Dongxu Wang, Xiaoqun Wang, Wei Xiong, Guangming Huang, Feng Gao, Yong Shen","doi":"10.1016/j.neuron.2025.01.030","DOIUrl":"10.1016/j.neuron.2025.01.030","url":null,"abstract":"<p><p>Neural hyperexcitability has been clinically associated with amyloid-β (Aβ) pathology and cognitive impairment in Alzheimer's disease (AD). Here, we show that decreased GABA<sub>A</sub> receptor (GABA<sub>A</sub>R) currents are linked to hippocampal granule cell hyperexcitability in the AD mouse model APP23. Elevated levels of β-secretase (BACE1), the β-secretase responsible for generating Aβ peptides, lead to aberrant cleavage of GABA<sub>A</sub>R β1/2/3 subunits in the brains of APP23 mice and AD patients. Moreover, BACE1-dependent cleavage of the β subunits leads to a decrease in GABA<sub>A</sub>R-mediated inhibitory currents in BACE1 transgenic mice. Finally, we show that the neural hyperexcitability, Aβ load, and spatial memory deficit phenotypes of APP23 mice are significantly reduced upon the granule cell expression of a non-cleavable β3 subunit mutant. Collectively, our study establishes that BACE1-dependent cleavage of GABA<sub>A</sub>R β subunits promotes the pathological hyperexcitability known to drive neurodegeneration and cognitive impairment in the AD brain, suggesting that prevention of the cleavage could slow disease progression.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":"1051-1064.e6"},"PeriodicalIF":14.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuronPub Date : 2025-04-01DOI: 10.1016/j.neuron.2025.03.010
Garret D Stuber, Valerie M Schwitzgebel, Christian Lüscher
{"title":"The neurobiology of overeating.","authors":"Garret D Stuber, Valerie M Schwitzgebel, Christian Lüscher","doi":"10.1016/j.neuron.2025.03.010","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.03.010","url":null,"abstract":"<p><p>Food intake serves to maintain energy homeostasis; however, overeating can result in obesity, which is associated with serious health complications. In this review, we explore the intricate relationship between overeating, obesity, and the underlying neurobiological mechanisms. We review the homeostatic and hedonic feeding systems, highlighting the role of the hypothalamus and reward systems in controlling food intake and energy balance. Dysregulation in both these systems leads to overeating, as seen in genetic syndromes and environmental models affecting appetite regulation when consuming highly palatable food. The concept of \"food addiction\" is examined, drawing parallels to drug addiction. We discuss the cellular substrate for addiction-related behavior and current pharmacological obesity treatments-in particular, GLP-1 receptor agonists-showcasing synaptic plasticity in the context of overeating and palatable food exposure. A comprehensive model integrating insights from addiction research is proposed to guide effective interventions for maladaptive feeding behaviors. Ultimately, unraveling the neurobiological basis of overeating holds promise for addressing the pressing public health issue of obesity.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuronPub Date : 2025-04-01DOI: 10.1016/j.neuron.2025.03.009
Norjin Zolboot, Yao Xiao, Jessica X Du, Marwan M Ghanem, Su Yeun Choi, Miranda J Junn, Federico Zampa, Zeyi Huang, Ian J MacRae, Giordano Lippi
{"title":"MicroRNA mechanisms instructing Purkinje cell specification.","authors":"Norjin Zolboot, Yao Xiao, Jessica X Du, Marwan M Ghanem, Su Yeun Choi, Miranda J Junn, Federico Zampa, Zeyi Huang, Ian J MacRae, Giordano Lippi","doi":"10.1016/j.neuron.2025.03.009","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.03.009","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) are critical for brain development; however, if, when, and how miRNAs drive neuronal subtype specification remains poorly understood. To address this, we engineered technologies with vastly improved spatiotemporal resolution that allow the dissection of cell-type-specific miRNA-target networks. Fast and reversible miRNA loss of function showed that miRNAs are necessary for Purkinje cell (PC) differentiation, which previously appeared to be miRNA independent, and identified distinct critical miRNA windows for dendritogenesis and climbing fiber synaptogenesis, structural features defining PC identity. Using new mouse models that enable miRNA-target network mapping in rare cell types, we uncovered PC-specific post-transcriptional programs. Manipulation of these programs revealed that the PC-enriched miR-206 and targets Shank3, Prag1, En2, and Vash1, which are uniquely repressed in PCs, are critical regulators of PC-specific dendritogenesis and synaptogenesis, with miR-206 knockdown and target overexpression partially phenocopying miRNA loss of function. Our results suggest that gene expression regulation by miRNAs, beyond transcription, is critical for neuronal subtype specification.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuronPub Date : 2025-03-26DOI: 10.1016/j.neuron.2025.03.004
Jens Rummens, Bilal Khalil, Günseli Yıldırım, Pedro Silva, Valentina Zorzini, Nicolas Peredo, Marta Wojno, Meine Ramakers, Ludo Van Den Bosch, Philip Van Damme, Kristofer Davie, Jelle Hendrix, Frederic Rousseau, Joost Schymkowitz, Sandrine Da Cruz
{"title":"TDP-43 seeding induces cytoplasmic aggregation heterogeneity and nuclear loss of function of TDP-43.","authors":"Jens Rummens, Bilal Khalil, Günseli Yıldırım, Pedro Silva, Valentina Zorzini, Nicolas Peredo, Marta Wojno, Meine Ramakers, Ludo Van Den Bosch, Philip Van Damme, Kristofer Davie, Jelle Hendrix, Frederic Rousseau, Joost Schymkowitz, Sandrine Da Cruz","doi":"10.1016/j.neuron.2025.03.004","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.03.004","url":null,"abstract":"<p><p>Cytoplasmic aggregation and nuclear depletion of TAR DNA-binding protein 43 (TDP-43) are hallmarks of several neurodegenerative disorders. Yet, recapitulating both features in cellular systems has been challenging. Here, we produced amyloid-like fibrils from recombinant TDP-43 low-complexity domain and demonstrate that sonicated fibrils trigger TDP-43 pathology in human cells, including induced pluripotent stem cell (iPSC)-derived neurons. Fibril-induced cytoplasmic TDP-43 inclusions acquire distinct biophysical properties, recapitulate pathological hallmarks such as phosphorylation, ubiquitin, and p62 accumulation, and recruit nuclear endogenous TDP-43, leading to its loss of function. A transcriptomic signature linked to both aggregation and nuclear loss of TDP-43, including disease-specific cryptic splicing, is identified. Cytoplasmic TDP-43 aggregates exhibit time-dependent heterogeneous morphologies as observed in patients-including compacted, filamentous, or fragmented-which involve upregulation/recruitment of protein clearance pathways. Ultimately, cell-specific progressive toxicity is provoked by seeded TDP-43 pathology in human neurons. These findings identify TDP-43-templated aggregation as a key mechanism driving both cytoplasmic gain of function and nuclear loss of function, offering a valuable approach to identify modifiers of sporadic TDP-43 proteinopathies.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuronPub Date : 2025-03-26DOI: 10.1016/j.neuron.2025.03.008
Carlo Scialò, Weijia Zhong, Somanath Jagannath, Oscar Wilkins, Davide Caredio, Marian Hruska-Plochan, Flavio Lurati, Martina Peter, Elena De Cecco, Luigi Celauro, Adriano Aguzzi, Giuseppe Legname, Pietro Fratta, Magdalini Polymenidou
{"title":"Seeded aggregation of TDP-43 induces its loss of function and reveals early pathological signatures.","authors":"Carlo Scialò, Weijia Zhong, Somanath Jagannath, Oscar Wilkins, Davide Caredio, Marian Hruska-Plochan, Flavio Lurati, Martina Peter, Elena De Cecco, Luigi Celauro, Adriano Aguzzi, Giuseppe Legname, Pietro Fratta, Magdalini Polymenidou","doi":"10.1016/j.neuron.2025.03.008","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.03.008","url":null,"abstract":"<p><p>Neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) results from both gain of toxicity and loss of normal function of the RNA-binding protein TDP-43, but their mechanistic connection remains unclear. Increasing evidence suggests that TDP-43 aggregates act as self-templating seeds, propagating pathology through the central nervous system via a prion-like cascade. We developed a robust TDP-43-seeding platform for quantitative assessment of TDP-43 aggregate uptake, cell-to-cell spreading, and loss of function within living cells, while they progress toward pathology. We show that both patient-derived and recombinant TDP-43 pathological aggregates were abundantly internalized by human neuron-like cells, efficiently recruited endogenous TDP-43, and formed cytoplasmic inclusions reminiscent of ALS/FTD pathology. Combining a fluorescent reporter of TDP-43 function with RNA sequencing and proteomics, we demonstrated aberrant cryptic splicing and a loss-of-function profile resulting from TDP-43-templated aggregation. Our data highlight known and novel pathological signatures in the context of seed-induced TDP-43 loss of function.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Molecular pathways and diagnosis in spatially resolved Alzheimer's hippocampal atlas.","authors":"Pan Wang, Lei Han, Lifang Wang, Quyuan Tao, Zhen Guo, Ting Luo, Youzhe He, Zhi Xu, Jiayi Yu, Yuyang Liu, Zihan Wu, Bin Xu, Bufan Jin, Yanrong Wei, Ying Yang, Mengnan Cheng, Yujia Jiang, Chen Tian, Huiwen Zheng, Zhongqin Fan, Peiran Jiang, Yue Gao, Juanli Wu, Shengpeng Wang, Bing Sun, Zheng Fang, Junjie Lei, Benyan Luo, Huiying Wen, Guoping Peng, Yuanchun Tang, Tao Yang, Jing Chen, Zhenkun Zhuang, Xinhui Su, Catherine Pan, Keqing Zhu, Yi Shen, Shiping Liu, Aimin Bao, Jianhua Yao, Jian Wang, Xun Xu, Xiao-Ming Li, Longqi Liu, Shumin Duan, Jing Zhang","doi":"10.1016/j.neuron.2025.03.002","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.03.002","url":null,"abstract":"<p><p>We employed Stereo-seq combined with single-nucleus RNA sequencing (snRNA-seq) to investigate the gene expression and cell composition changes in human hippocampus with or without Alzheimer's disease (AD). The transcriptomic map, with single-cell precision, unveiled AD-associated alterations with spatial specificity, which include the following: (1) elevated synapse pruning gene expression in the fimbria of AD, with disrupted microglia-astrocyte communication likely leading to disorganized synaptic structure; (2) a globally increased energy generation in the cornu ammonis (CA) region, with varying degrees across its subregions; (3) a significant reduction in the number of CA1 neurons in AD, while CA4 neurons remained largely unaffected, potentially due to gene alterations in CA4 conferring resilience to AD; and (4) aggravated amyloid-beta (Aβ) plaques in CA1 and stratum lucidum, radiatum, and moleculare (SLRM), and integration of Stereo-seq map with Aβ staining revealed a sequential enrichment of microglia and astrocytes around Aβ plaques. Finally, reduced brain-derived extracellular vesicles carrying cholecystokinin (CCK) and peripheral myelin protein 2 (PMP2) in AD plasma highlighted their diagnostic potential for clinical applications.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NeuronPub Date : 2025-03-24DOI: 10.1016/j.neuron.2025.03.003
Yilong Wang, Lebo Zhou, Nan Wang, Baoshan Qiu, Di Yao, Jie Yu, Miaoqing He, Tong Li, Yufeng Xie, Xiaoqian Yu, Zhanying Bi, Xiangli Sun, Xunming Ji, Zhen Li, Dapeng Mo, Woo-Ping Ge
{"title":"Comprehensive characterization of metabolic consumption and production by the human brain.","authors":"Yilong Wang, Lebo Zhou, Nan Wang, Baoshan Qiu, Di Yao, Jie Yu, Miaoqing He, Tong Li, Yufeng Xie, Xiaoqian Yu, Zhanying Bi, Xiangli Sun, Xunming Ji, Zhen Li, Dapeng Mo, Woo-Ping Ge","doi":"10.1016/j.neuron.2025.03.003","DOIUrl":"https://doi.org/10.1016/j.neuron.2025.03.003","url":null,"abstract":"<p><p>Metabolism is vital for brain function. However, a systematic investigation to understand the metabolic exchange between the human brain and circulatory system has been lacking. Here, we compared metabolomes and lipidomes of blood samples from the cerebral venous sinus and femoral artery to profile the brain's uptake and release of metabolites and lipids (1,365 metabolites and 140 lipids). We observed a high net uptake of glucose, taurine, and hypoxanthine and identified glutamine and pyruvate as significantly released metabolites by the brain. Triacylglycerols are the most prominent class of lipid consumed by the brain. The brain with cerebral venous sinus stenosis (CVSS) consumed more glucose and lactate and released more glucose metabolism byproducts than the brain with cerebral venous sinus thrombosis (CVST). Our data also showed age-related alterations in the uptake and release of metabolites. These results provide a comprehensive view of metabolic consumption and production processes within the human brain.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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