Journal of Neurochemistry最新文献

{"title":"Ganaxolone Reverses the Effect of Amyloid β-Induced Neurotoxicity by Regulating the Liver X Receptor Expression in APP Transfected SH-SY5Y Cells and Murine Model of Alzheimer's Disease","authors":"Divya,&nbsp;Mohammed Faruq,&nbsp;Sheikh Sana Nazir,&nbsp;Pooja Kaushik,&nbsp;Suhel Parvez,&nbsp;Divya Vohora","doi":"10.1111/jnc.70007","DOIUrl":"https://doi.org/10.1111/jnc.70007","url":null,"abstract":"<div>\u0000 \u0000 <p>Inhibiting β-amyloid aggregation and enhancing its clearance are the key strategies in Alzheimer's disease (AD) treatment. Liver X receptors (LXRs) plays a crucial role in cholesterol homeostasis and inflammation, and their activation can clear Aβ aggregates in AD. Allopregnanolone, a neurosteroid, positively influences AD through LXR regulation, while ganaxolone, its synthetic analog, is known for its neuroprotective properties. This study explores the effect of ganaxolone on LXR activation and regulation of genes involved in mitigating Aβ toxicity and tauopathy in SH-SY5Y cells transfected with APP695 Swe/Ind plasmid and an Aβ1–42 induced AD mouse model. Molecular docking stimulations indicated ganaxolone's binding and interaction with LXRβ. Subsequently, transfected neuronal cells exhibited increased mRNA levels of APP, TNF-α and IL-1β, decreased cell viability, reduced MMP and altered protein expression of Aβ, LXR, BCL-2, APOE, ABCA1, along with increased levels of mROS, Bax, and caspase 3 activity. Ganaxolone treatment significantly abrogated Aβ-induced effect in transfected neuronal cells by enhancing LXRβ expression, inducing LXR:RXR colocalization, thereby increasing APOE and ABCA1 expression. It also decreased tau mRNA levels in transfected cells. Importantly, in AD mice, ganaxolone ameliorated cognitive impairment, reduced Aβ toxicity, tau levels, and neuroinflammatory markers, restored mitochondrial function, and decreased neuronal apoptosis. Taken together, these novel results highlight the central role of LXR in mediating Aβ-induced toxicity and provide preclinical evidence for ganaxolone as a potential agent to reduce toxicity in an LXR-dependent manner. This may serve as a promising treatment strategy to slow or prevent neurodegeneration in AD patients.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389047","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":"Hunger Games: A Modern Battle Between Stress and Appetite","authors":"Whitnei Smith,&nbsp;Estefania P. Azevedo","doi":"10.1111/jnc.70006","DOIUrl":"https://doi.org/10.1111/jnc.70006","url":null,"abstract":"<p>Stress, an evolutionarily adaptive mechanism, has become a pervasive challenge in modern life, significantly impacting feeding-relevant circuits that play a role in the development and pathogenesis of eating disorders (EDs). Stress activates the hypothalamic–pituitary–adrenal (HPA) axis, disrupts specific neural circuits, and dysregulates key brain regions, including the hypothalamus, hippocampus, and lateral septum. These particular structures are interconnected and key in integrating stress and feeding signals, modulating hunger, satiety, cognition, and emotional coping behaviors. Here we discuss the interplay between genetic predispositions and environmental factors that may exacerbate ED vulnerability. We also highlight the most commonly used animal models to study the mechanisms driving EDs and recent rodent studies that emphasize the discovery of novel cellular and molecular mechanisms integrating stress and feeding signals within the hippocampus–lateral septum–hypothalamus axis. In this review, we discuss the role of gut microbiome, an emerging area of research in the field of EDs and unanswered questions that persist and hinder the scientific progress, such as why some individuals remain resilient to stress while others become at high risk for the development of EDs. We finally discuss the need for future research delineating the impact of specific stressors on neural circuits, clarifying the relevance and functionality of hippocampal–septal–hypothalamic connectivity, and investigating the role of key neuropeptides such as CRH, oxytocin, and GLP-1 in human ED pathogenesis. Emerging tools like single-cell sequencing and advanced human imaging could uncover cellular and circuit-level changes in brain areas relevant for feeding in ED patients. Ultimately, by integrating basic and clinical research, science offers promising avenues for developing personalized, mechanism-based treatments targeting maladaptive eating behavior for patients suffering from EDs.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389050","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":"Oxidative Stress Suppresses Trk Signaling While Stimulating JNK-Mediated Endocytosis and Cleavage of p75NTR: A Targetable Pathway for Neuroprotection in a Parkinson's Disease Model","authors":"Poshan V. Pokharel,&nbsp;Aaron M. Newchurch,&nbsp;Sunny C. Overby,&nbsp;Cassidy A. Spease,&nbsp;Isaac T. Perkins,&nbsp;Lorelei G. Darzi,&nbsp;Nabin Ghimire,&nbsp;Ahmed Lawan,&nbsp;Bradley R. Kraemer","doi":"10.1111/jnc.70010","DOIUrl":"https://doi.org/10.1111/jnc.70010","url":null,"abstract":"<div>\u0000 \u0000 <p>The p75 Neurotrophin Receptor (p75^NTR) is a multifunctional transmembrane protein that mediates neuronal responses to pathological conditions in specific regions of the nervous system. In many biological contexts, p75^NTR signaling is initiated through sequential cleavage of the receptor by α- and γ-secretases, which releases receptor fragments for downstream signaling. Our previous research demonstrated that proteolytic processing of p75^NTR in this manner is stimulated by oxidative stress in Lund Human Mesencephalic (LUHMES) cells, a dopaminergic neuronal cell line derived from human mesencephalic tissue. Considering the vulnerability of dopaminergic neurons in the ventral mesencephalon to oxidative stress and neurodegeneration associated with Parkinson's disease (PD), we investigated the role of this signaling cascade in neurodegeneration and explored cellular processes that govern oxidative stress-induced p75^NTR signaling. In the present study, we provide evidence that oxidative stress induces cleavage of p75^NTR by promoting c-Jun N-terminal Kinase (JNK)-dependent internalization of p75^NTR from the cell surface. This activation of p75^NTR signaling is counteracted by tropomyosin-related kinase (Trk) receptor signaling; however, oxidative stress leads to Trk receptor downregulation, thereby enhancing p75^NTR processing. Importantly, we demonstrate that this pathway can be inhibited by LM11a-31, a small molecule modulator of p75^NTR, thereby conferring protection against neurodegeneration. Treatment with LM11a-31 significantly reduced p75^NTR cleavage and neuronal death associated with oxidative stress. These findings reveal novel mechanisms underlying activation of p75^NTR in response to oxidative stress, underscore a key role for p75^NTR in dopaminergic neurodegeneration, and highlight p75^NTR as a potential therapeutic target for reducing neurodegeneration in PD.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389051","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":"Direct Current Stimulation (DCS) Modulates Lipid Metabolism and Intercellular Vesicular Trafficking in SHSY-5Y Cell Line: Implications for Parkinson's Disease","authors":"Marco Piccoli,&nbsp;Luisa Barbato,&nbsp;Natale Vincenzo Maiorana,&nbsp;Alessandra Mingione,&nbsp;Francesca Raimondo,&nbsp;Marco Ghirimoldi,&nbsp;Federica Cirillo,&nbsp;Mattia Schiepati,&nbsp;Domenico Salerno,&nbsp;Luigi Anastasia,&nbsp;Elisabetta Albi,&nbsp;Marcello Manfredi,&nbsp;Tommaso Bocci,&nbsp;Alberto Priori,&nbsp;Paola Signorelli","doi":"10.1111/jnc.70014","DOIUrl":"https://doi.org/10.1111/jnc.70014","url":null,"abstract":"<p>The modulation of the brain's electrical activity for therapeutic purposes has recently gained attention, supported by the promising results obtained through the non-invasive application of transcranial direct current stimulation (tDCS) in the treatment of neurodegenerative and neurological diseases. To optimize therapeutic efficacy, it is crucial to investigate the cellular and molecular effects of tDCS. This will help to identify important biomarkers, predict patient's response and develop personalized treatments. In this study, we applied direct current stimulation (DCS) to a neural cell line, using mild currents over short periods of time (0.5 mA, 20 min), with 24-h intervals. We observed that DCS induced changes in the cellular lipidome, with transient effects observed after a single stimulation (lasting 24 h) and more significant, long-lasting effects (up to 72 h) after repeated stimulation cycles. In neural cells, multiple DCS treatment modulated structural membrane lipids (PE, PS, PI), downregulated glycerol lipids with ether-linked fatty acids and pro-inflammatory lipids (ceramides and lyso-glycerophospholipids) (<i>p</i> ≤ 0.005). Multiple DCS sessions altered transcriptional activity by decreasing the expression of inflammatory cytokines (TNF-α, <i>p</i> ≤ 0.05; IL-1β, <i>p</i> ≤ 0.01), while increasing the expression of neuroprotective factors such as heme oxygenase-1 (<i>p</i> ≤ 0.0001) and brain-derived neurotrophic factor (<i>p</i> ≤ 0.05), as well as proteins involved in vesicular transport (SNARE, sorting nexins and seipin and α-synuclein; <i>p</i> ≤ 0.05). In addition, DCS enhanced the release of extracellular vesicles, with repeated stimulations significantly increasing the release of exosomes threefold. In conclusion, while a single electrical stimulation induces transient metabolic changes with limited phenotypic effects, repeated applications induce a broader and deeper modulation of lipid species. This may lead to a neuroprotective and neuroplasticity-focussed transcriptional profile, potentially supporting the therapeutic effects of tDCS at the cellular and molecular level in patients..\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380204","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":"PPARβ/δ Activation Improves Corticosterone-Induced Oxidative Stress Damage in Astrocytes by Targeting UBR5/ATM Signaling","authors":"Juan Ji,&nbsp;Ye-Fan Chen,&nbsp;Chen Hong,&nbsp;Xue-Wei Ren,&nbsp;Hang Xu,&nbsp;Zhen-Yu Cai,&nbsp;Yin-Feng Dong,&nbsp;Xiu-Lan Sun","doi":"10.1111/jnc.70013","DOIUrl":"https://doi.org/10.1111/jnc.70013","url":null,"abstract":"<div>\u0000 \u0000 <p>Oxidative stress-mediated astrocytic damage contributes to nerve injury and the development of depression, especially under stress conditions. Peroxisomes and pexophagy are essential for balancing oxidative stress and protein degradation products. Our previous findings suggest that peroxisome proliferators-activated receptor β/δ (PPARβ/δ) activation significantly alleviates depressive behaviors by preventing astrocytic injury. However, the underlying mechanisms remain unclear. In the present study, we established oxidative injury by treating astrocytes with corticosterone. Subsequently, PPARβ/δ agonists and antagonists were applied to determine the effects of PPARβ/δ on balancing peroxisomes and pexophagy in astrocytes. The PPARβ/δ agonist (GW0742) significantly improved cell viability and decreased intracellular reactive oxygen species (ROS) production induced by corticosterone, while pretreatment with the PPARβ/δ, antagonist GSK3787 reversed the effects of GW0742. Moreover, activating PPARβ/δ promoted peroxisomal biogenesis factor 5 (PEX5)-mediated pexophagy by enhancing the phosphorylation of ataxia-telangiectasia mutated (ATM) kinase. Conversely, blocking PPARβ/δ with GSK3787 partially abolished the effects of GW0742. Further investigations demonstrated that activation of PPARβ/δ not only induced transcription of the ubiquitin protein ligase E3 component n-recognin 5 (UBR5) but also enhanced the interaction between PPARβ/δ and UBR5, contributing to ATM interactor (ATMIN) degradation, and increased phosphorylated ATM kinase levels. Therefore, this study revealed that activating PPARβ/δ improves corticosterone-induced oxidative damage in astrocytes by enhancing pexophagy. PPARβ/δ directly interacts with UBR5 to facilitate ATMIN degradation and promotes ATM phosphorylation, thereby maintaining the balance between peroxisomes and pexophagy. These findings suggest that PPARβ/δ is a potential target for promoting pexophagy in astrocytes upon stress.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362858","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":"mTORC2 Regulates Actin Polymerization in Auditory Cells","authors":"Michael Lanz,&nbsp;Maurizio Cortada,&nbsp;Yu Lu,&nbsp;Soledad Levano,&nbsp;Daniel Bodmer","doi":"10.1111/jnc.70012","DOIUrl":"https://doi.org/10.1111/jnc.70012","url":null,"abstract":"<div>\u0000 \u0000 <p>Mammalian target of rapamycin complex 2 (mTORC2) is essential for hearing by regulating auditory hair cell structure and function. However, mechanistic details of how mTORC2 regulates intracellular processes in sensory hair cells have not yet been clarified. To further elucidate the role of mTORC2 in auditory cells, we generated a <i>Rictor</i> knockout cell line from HEI-OC1 auditory cells. mTORC2-deficient auditory cells exhibited significant alterations in actin cytoskeleton morphology and decreased proliferation rates. Additionally, we observed a reduction in phosphorylation of protein kinase C alpha (PKCα) and disrupted actin polymerization in mTORC2-deficient cells. Using proteomics, we found that mTORC2 disruption altered expression of cytoskeleton-related proteins in auditory cells. These findings provide valuable mechanistic insights into the functional role of mTORC2 in auditory cells, potentially opening new perspectives to address sensorineural hearing loss.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362859","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":"Genetic Markers of Postmortem Brain Iron","authors":"Marilyn C. Cornelis,&nbsp;Amir Fazlollahi,&nbsp;David A. Bennett,&nbsp;Julie A. Schneider,&nbsp;Scott Ayton","doi":"10.1111/jnc.16309","DOIUrl":"https://doi.org/10.1111/jnc.16309","url":null,"abstract":"<p>Brain iron (Fe) dyshomeostasis is implicated in neurodegenerative diseases. Genome-wide association studies (GWAS) have identified plausible loci correlated with peripheral levels of Fe. Systemic organs and the brain share several Fe regulatory proteins but there likely exist different homeostatic pathways. We performed the first GWAS of inductively coupled plasma mass spectrometry measures of postmortem brain Fe from 635 Rush Memory and Aging Project (MAP) participants. Sixteen single nucleotide polymorphisms (SNPs) associated with Fe in at least one of four brain regions were measured (<i>p</i> &lt; 5 × 10⁻⁸). Promising SNPs (<i>p</i> &lt; 5 × 10⁻⁶) were followed up for replication in published GWAS of blood, spleen, and brain imaging Fe traits and mapped to candidate genes for targeted cortical transcriptomic and epigenetic analysis of postmortem Fe in MAP. Results for SNPs previously associated with other Fe traits were also examined. Ninety-eight SNPs associated with postmortem brain Fe were at least nominally (<i>p</i> &lt; 0.05) associated with one or more related Fe traits. Most novel loci identified had no direct links to Fe regulatory pathways but rather endoplasmic reticulum-Golgi trafficking (<i>SORL1, SORCS2, MARCH1, CLTC</i>), heparan sulfate (<i>HS3ST4, HS3ST1</i>), and coenzyme A (<i>SLC5A6, PANK3</i>); supported by nearest gene function and omic analyses. We replicated (<i>p</i> &lt; 0.05) several previously published Fe loci mapping to candidate genes in cellular and systemic Fe regulation. Finally, novel loci (<i>BMAL, COQ5, SLC25A11</i>) and replication of prior loci (<i>PINK1, PPIF, LONP1</i>) lend support to the role of circadian rhythms and mitochondria function in Fe regulation more generally. In summary, we provide support for novel loci linked to pathways that may have greater relevance to brain Fe accumulation; some of which are implicated in neurodegeneration. However, replication of a subset of prior loci for blood Fe suggests that genetic determinants or biological pathways underlying Fe accumulation in the brain are not completely distinct from those of Fe circulating in the periphery.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.16309","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362465","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":"Prenatal Alcohol Consumption Alters Protein Fingerprint in Umbilical Cord Blood Serum and Induces Brain Microvascular Endothelial Cell Dysfunction","authors":"Paula Silva Lacerda Almeida,&nbsp;Dayana Araújo,&nbsp;Juliana Minardi Nascimento,&nbsp;Alex C. Manhães,&nbsp;Nilson Ramires Jesus,&nbsp;Joice Stipursky","doi":"10.1111/jnc.70015","DOIUrl":"https://doi.org/10.1111/jnc.70015","url":null,"abstract":"<div>\u0000 \u0000 <p>Consumption of alcoholic beverages during pregnancy is directly related to the establishment of fetal alcohol spectrum disorders (FASD), which includes craniofacial changes, body growth restriction, and neurodevelopment impairments. Proper functioning of the central nervous system (CNS) depends on blood–brain barrier (BBB) development, which is formed by interactions of vascular endothelial cells, pericytes, astrocytes, and basal lamina. Gestational exposure to ethanol has been demonstrated to impair CNS development; however, little is known about ethanol modulation of blood circulating factors and impacts on human developing BBB. Here we investigated the prevalence of alcohol consumption during pregnancy and found that 27% of pregnant women reported alcohol consumption, mainly in the first trimester. Control and alcohol-exposed newborns showed no differences in weight, length, and appearance, pulse, grimace, activity, respiration (APGAR) score at birth. In vitro, we cultivated human brain microcapillary endothelial cells (HBMEC) and treated with umbilical cord blood serum (UCBS) from control (S-Control) newborns or ethanol-exposed ones (S-Ethanol). S-Ethanol treatment induced 68% and 38% decreases in protein levels of ZO-1 (tight junction) and GLUT-1 (glucose transporter type-1), respectively, increased endothelial monolayer permeability, migratory potential impairment, and changes in angiogenesis-related secreted proteins profile, compared to S-Control treatments. UCBS proteomics revealed a total of 392 proteins, 10 exclusively found in S-Ethanol, mostly related to innate and adaptive immunity and tissue injury response. These results suggest that gestational exposure to ethanol contributes to blood altered protein profiles triggering BBB endothelial.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362466","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":"Transcript and Lipid Profile Alterations in Astrocyte-Neuron Mitochondrial Transfer Under Lipopolysaccharide Exposure: An In Vitro Study","authors":"Yufei Kan,&nbsp;Hong Wang,&nbsp;Huaying Lin,&nbsp;Yongfa Li,&nbsp;Shuaijie Pei,&nbsp;Yan Cui,&nbsp;Keliang Xie,&nbsp;Hongguang Chen,&nbsp;Yonghao Yu","doi":"10.1111/jnc.70003","DOIUrl":"https://doi.org/10.1111/jnc.70003","url":null,"abstract":"<p>Sepsis-associated encephalopathy (SAE) is a brain dysfunction for which no effective therapy currently exists. Recent studies suggest that transferring mitochondria from astrocytes to neurons may benefit SAE patients, though the underlying mechanism remains unclear. We cultured astrocytes and neurons from mice in vitro. Astrocytes were stimulated with lipopolysaccharide (LPS) for 24 h, and the astrocyte-conditioned medium (ACM) was collected. Neuronal cultures were then treated with ACM or mitochondria-depleted ACM (mdACM) for further analysis. Mitochondrial transfer was examined under a fluorescence microscope. Western blotting analyzed the protein expression of genes related to apoptosis and mitochondrial metabolism. RNA sequencing and mass spectrometry were employed to investigate the mechanisms underlying mitochondrial transfer. Astrocyte-derived mitochondria migrated toward and connected with LPS-exposed neurons. The addition of ACM significantly attenuated LPS-induced alterations in the proteins linked to apoptosis and mitochondrial dynamics. RNA sequencing revealed notable alterations in the transcript profile of neurons upon ACM treatment, highlighting the involvement of mitochondria metabolism, inflammation, and apoptosis-related factors. Additionally, mitochondrial transfer modified the lipid composition of neurons, increasing phosphatidylserine levels, which correlated with neuroinflammation and enriched pathways related to cytokine and MAPK signaling. Our findings suggest that astrocyte-neuron mitochondrial transfer holds therapeutic potential for alleviating SAE, possibly through the anti-inflammatory effects of lipids, particularly phosphatidylserine.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143112161","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":"Focused Ultrasound Modulates Dopamine in a Mesolimbic Reward Circuit","authors":"Greatness Olaitan,&nbsp;Mallikarjunarao Ganesana,&nbsp;Andrew Strohman,&nbsp;Wendy J. Lynch,&nbsp;Wynn Legon,&nbsp;B. Jill Venton","doi":"10.1111/jnc.70001","DOIUrl":"https://doi.org/10.1111/jnc.70001","url":null,"abstract":"<p>Dopamine is a neurotransmitter that plays a significant role in reward and motivation. Dysfunction in the mesolimbic dopamine pathway has been linked to a variety of psychiatric disorders, including addiction. Low-intensity focused ultrasound (LIFU) has demonstrated effects on brain activity, but how LIFU affects dopamine neurotransmission is not known. Here, we applied three different intensities (6.5, 13, and 26 W/cm² <i>I</i>_SPPA) of 2-min LIFU to the prelimbic cortex (PLC) and measured dopamine in the nucleus accumbens (NAc) core using fast-scan cyclic voltammetry. Two minutes of LIFU sonication at 13 W/cm² to the PLC significantly reduced dopamine release by ~50% for up to 2 h. However, double the intensity (26 W/cm²) resulted in less inhibition (~30%), and half the intensity (6.5 W/cm²) did not result in any inhibition of dopamine. Anatomical controls applying LIFU to the primary somatosensory cortex did not change NAc core dopamine, and applying LIFU to the PLC did not affect dopamine release in the caudate or NAc shell. Histological evaluations showed no evidence of cell damage or death. Modeling temperature rise demonstrates a maximum temperature change of 0.5°C with 13 W/cm², suggesting that modulation is not due to thermal mechanisms. These studies show that LIFU at a moderate intensity provides a noninvasive, high spatial resolution means to modulate specific mesolimbic circuits that could be used in future studies to target and repair pathways that are dysfunctional in addiction and other psychiatric diseases.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143112162","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}