ACS Chemical Neuroscience最新文献

{"title":"Correction to \"Discovery of ONO-2920632 (VU6011887): A Highly Selective and CNS Penetrant TREK-2 (TWIK-Related K+ Channel 2) Preferring Activator <i>In Vivo</i> Tool Compound\".","authors":"Kentaro Yashiro, Yuzo Iwaki, Hirohito Urata, Masaya Kokubo, Takahiro Mori, Yoko Sekioka, Koichi Isami, Junya Kato, Joshua Wieting, Kevin M McGowan, Thomas M Bridges, Olivier Boutaud, Darren W Engers, Jerod S Denton, Haruto Kurata, Craig W Lindsley","doi":"10.1021/acschemneuro.5c00409","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00409","url":null,"abstract":"","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309240","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":"Unraveling the Role of THRIL/miR-137 in Fine-Tuning the Immunological Transcriptional Loop STAT4/STAT6/GATA3 in Multiple Sclerosis: Implications on Neurological Complications and Disease Subtypes.","authors":"Ghada Ayeldeen, Bahaa Mohammed Badr, Aeshah A Awaji, Dalia A Gaber, Doaa Abdellatif Elelwany, Abdulrhman Khaled Al Abdulqader, Olfat G Shaker, Mai A Abd-Elmawla","doi":"10.1021/acschemneuro.5c00299","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00299","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is an autoimmune disease associated with neurological impairments. The study aimed to evaluate the role of the noncoding RNAs THRIL/miR-137 in MS pathogenesis via studying their effect on the immunological transcriptional loop STAT4/STAT6/GATA3, and their association with MS-related neurological impairments and disease subtypes. Overall, 148 participants were included: 74 MS patients and 74 matched healthy controls. Gene expressions of THRIL, miR-137, STAT4, STAT6, and GATA3 were assessed using reverse transcription quantitative polymerase chain reaction (RT-qPCR). The potential protein interaction networks of these genes were predicted using bioinformatic analysis. Compared with the control group, THRIL, STAT4, and GATA3 were upregulated, whereas miR-137 and STAT6 were downregulated in MS patients. Furthermore, THRIL, STAT4, and GATA3 were upregulated, while miR-137 and STAT6 were downregulated in MS patients with Expanded Disability Status Scale (EDSS) ≥ 3.5, relative to patients with EDSS < 3.5. Similarly, THRIL, STAT4, and GATA3 were upregulated, while miR-137 and STAT6 were downregulated in Secondary Progressive MS (SPMS) patients relative to Relapsing-Remitting MS (RRMS). Notably, receiver operating characteristic (ROC) curve analysis revealed that THRIL, miR-137, and STAT4/STAT6/GATA3 can be used in differentiating between MS patients with neurological impairments as well as MS subtypes. Significantly, logistic analysis revealed that THRIL, miR-137, and STAT4/STAT6/GATA3 could act as predictors to diagnose MS and the associated neurological impairments. In conclusion, the study demonstrated for the first time the role of THRIL/miR-137 in regulating the immunological transcriptional loop STAT4/STAT6/GATA3, which may contribute to neurological complications. These findings provide insights into MS pathogenesis and highlight the potential of these genes as biomarkers or therapeutic targets.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309243","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":"Modulation of Prostaglandin-Endoperoxide Synthase 1 by Caulis Sinomenii: A Novel Approach to Alleviating Diabetic Peripheral Neuropathy Through Apoptosis Inhibition and Anti-inflammatory Effects.","authors":"Lin Zhu, Ji Chen, Yuan Liu, Wen Chen, Xinxin Liu, Fengrui Yang","doi":"10.1021/acschemneuro.5c00226","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00226","url":null,"abstract":"<p><p>Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of diabetes, characterized by neurodegeneration and chronic pain. This study investigates the potential of Caulis Sinomenii (CS), a traditional Chinese medicine, to alleviate DPN through the modulation of prostaglandin-endoperoxide synthase 1 (PTGS1), microglial apoptosis, and inflammation. DPN was induced in mice using streptozotocin (STZ). Pain sensitivity was assessed using the hot plate and mechanical allodynia tests. Inflammatory cytokines (IL-6, TNF-α) were measured by ELISA. Histopathology and TUNEL staining were used to evaluate tissue damage and apoptosis. Network pharmacology and molecular docking identified key targets, including PTGS1. In vitro, BV2 microglial cells were treated with CS to assess cell viability, apoptosis, and inflammation. CS significantly reduced pain sensitivity, inflammatory cytokines, and neuronal apoptosis in DPN mice. Network analysis highlighted PTGS1 as a critical target of CS. In vitro, CS downregulated PTGS1 and reduced apoptosis while suppressing inflammatory responses. CS alleviates DPN by modulating PTGS1 expression, inhibiting apoptosis, and reducing inflammation. These findings suggest CS as a promising therapeutic for DPN.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300536","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":"Modulation of hIAPP Fibrillation by Rationally Designed Hexapeptides Revealed by Molecular Dynamics and Experimental Investigations.","authors":"Diksha Rani, Nitesh Priyadarshi, Nitin Kumar Singhal, Bhupesh Goyal","doi":"10.1021/acschemneuro.5c00269","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00269","url":null,"abstract":"<p><p>The misfolding and aggregation of 37-residue neuropancreatic hormone hIAPP (human islet amyloid polypeptide) to cytotoxic aggregates comprising oligomers, protofibrils, and mature fibrils have been linked to the pathogenesis of T2D (type 2 diabetes). Scrocchi et al. (J. Mol. Biol. 2002, 318, 697-706) identified a fragment peptide, SNNFGA (residues 20-25) from the amyloidogenic core region (Ser20-Ser29) of hIAPP as a potential inhibitor of hIAPP fibrillation. In this work, a library of 863 hexapeptides based on SNNFGA has been computationally designed and evaluated for antiaggregation activity against hIAPP fibrillation. The MM-PBSA analysis depicted that peptides TNNWPL (-42.69 ± 1.88 kcal/mol), TQNWAP (-41.82 ± 2.28 kcal/mol), and TQNWVP (-39.38 ± 1.63 kcal/mol) bind to hIAPP with higher affinity than SNNFGA (-27.15 ± 1.83 kcal/mol). Notably, TQNWVP displays a more pronounced inhibition effect than other peptides due to its ability to block the conformational transformation of hIAPP from a random coil to an aggregation-competent β-sheet conformation. The <i>in silico</i> assessment of ADMET values for the designed peptides lies within the range for therapeutic candidates, and the peptides display higher half-life than SNNFGA. To corroborate the computational findings, the peptides were evaluated for their potential to block hIAPP fibrillation using ThT fluorescence assay, DLS, and TEM. Among the synthesized peptides, TQNWVP exhibited the highest inhibitory activity (Inhibition = 75%, IC₅₀ = 6.19 ± 0.31 μM) against hIAPP fibrillation consistent with the computational results. Importantly, DLS analysis confirmed that TQNWVP reduced the size of hIAPP aggregates. Peptides exhibited a satisfactory safety-efficacy profile and efficiently alleviated hIAPP aggregate-induced cytotoxicity in rat insulinoma (INS-1) and human embryonic kidney (HEK293) cells. The combined <i>in silico</i> and <i>in vitro</i> studies in this work identified a new peptide, TQNWVP, as an efficient inhibitor of hIAPP aggregation. Furthermore, illumination of the inhibitory mechanism of SNNFGA and top hit peptides (TNNWPL, TQNWAP, and TQNWVP) against hIAPP aggregation holds significant promise for future therapeutic interventions against hIAPP fibrillation in T2D.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309241","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":"Neuroprotective Effects of a Benzofuran-Containing Selenium in a Mouse Alzheimer's Disease Model: Molecular, Biochemical, and Behavioral Analyses.","authors":"Tácia Katiane Hall, Mariana Parron Paim, Pâmella da Costa, Amanda Rebelo de Azevedo, Vanessa Nascimento, José Sebastião Santos Neto, Fernanda Severo Sabedra Sousa, Tiago Veiras Collares, Fabiana Kommling Seixas, César Augusto Brüning, Cristiani Folharini Bortolatto","doi":"10.1021/acschemneuro.5c00139","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00139","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder mainly characterized by progressive cognitive decline, for which effective treatments remain limited, and selenium is known for its neuroprotective actions. Thus, this study evaluated the neuroprotective effects of the compound 2-(((3-trifluoromethyl)phenyl(selenyl)methyl)-2,3-dihydrobenzofuran (TFSeB) in a streptozotocin (STZ)-induced AD model in male Swiss mice. The animals received intracerebroventricular injections of STZ (3 mg/kg, a neurotoxic agent) to induce cognitive deficits, followed by treatment with TFSeB (1 and 5 mg/kg, intragastrically). Behavioral tests revealed that, like positive control (memantine), the compound TFSeB improved memory performance in the Y-maze, novel object recognition, and passive avoidance tests, suggesting its ability to counteract STZ-induced memory impairments. Biochemical analyses showed that the compound reduced oxidative stress markers in the prefrontal cortex and cerebellum of mice exposed to STZ, including TBARS, ROS, and nitrite levels while increasing NPSH. STZ induced an increase in monoamine oxidase B (MAO-B) activity in the hippocampus and cortex, as well as in acetylcholinesterase (AChE) activity in the cortex and cerebellum, which were reverted by TFSeB. Hippocampal RT-qPCR molecular analyses revealed that TFSeB modulated apoptosis-related proteins by increasing BCL-2 and decreasing BAX expression, favoring neuronal survival. Moreover, TFSeB increased brain-derived neurotrophic factor (BDNF) and nuclear factor erythroid 2 (NRF2), targets associated with neuroprotection. The compound also decreased key inflammatory and neurodegenerative markers, including nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), and glycogen synthase kinase 3 beta (GSK3B). In conclusion, the compound TFSeB demonstrates promising protective effects in a STZ-induced AD model by modulating key neurochemical, oxidative, and neuroinflammatory pathways.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309242","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":"Properties of Acute Activation and Inhibition of the β3 Homomeric GABA_A Receptor Mediated by Protonation of Conserved Histidine Residues.","authors":"Spencer R Pierce, Allison L Germann, Yu Zhou, Saumith L Menon, Xinghan Gu, Christopher J Lingle, Alex S Evers, Joe Henry Steinbach, Gustav Akk","doi":"10.1021/acschemneuro.5c00256","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00256","url":null,"abstract":"<p><p>GABA_A receptors are inhibitory transmitter-gated ion channels formed of various combinations of the 19 homologous subunits cloned to date. Changes in extracellular pH have been shown to directly activate the receptor or modulate its activity elicited by a chemical agonist, but the direction and magnitude of the effect depend on the subunit composition of the receptor. Here, we investigated the acute effect of protonation on the function of the human β3 homomeric GABA_A receptor. We show that the reduction of the pH of the extracellular bath solution directly activates this receptor. H⁺ concentration-response data yielded a pEC₅₀ of ∼6 (EC₅₀ ∼ 1 μM). The probability of being in the active state ranged from 0.005 at pH 8.5 to 0.37 at saturating [H⁺]. The activating effect of H⁺ was rapidly reversible, and H⁺-activated receptors showed minimal desensitization. Mutation of the conserved histidine residue in the 17' position in the second membrane-spanning helix (H267) to alanine abolished H⁺-elicited activation, revealing inhibition of constitutive activity at low pH that, in its turn, was removed by additionally introducing the H107G mutation in the extracellular domain. We propose that the previously reported constitutive activity of the β3 receptor at physiological pH reflects H⁺-elicited activity, reflecting the net effect of protonation of H267 and H107 residues.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300537","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":"Obacunone Alleviates Thalamic Pain via Promoting LCN2-Mediated Phagocytosis of Astrocytes in Mice.","authors":"Yue-Rong Li, Lin-Lin Xie, Hao-Bin Cai, Zhao-Hui Dang, Li-Ling Li, Xu Wang, Yun-Wei Lu, Zi-Cheng Zhang, Song Gao, Jia-Ye Liu, Long-Sheng Xu, Qin-Li Feng, Xiu-De Qin, Fan Bu","doi":"10.1021/acschemneuro.5c00371","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00371","url":null,"abstract":"<p><p>Thalamic pain is a common pain syndrome following thalamic stroke with limited therapeutic options. Though the pathogenesis of thalamic pain is far from clear, accumulating studies have demonstrated that the ectopic activity of thalamic glial cells contributes to allodynia development after thalamic hemorrhage (TH). Obacunone (Oba) is a highly oxygenated triterpenoid extracted from a Chinese edible medicinal herb, Phellodendron, with a broad spectrum of biological activities in mediating glial depolarization. We herein investigated the analgesic effect of Oba and its underlying reasons on the collagenase-induced TH model of mice. We found that Oba suppressed TH-induced allodynia dose-dependently. Mechanistically, gavage Oba promoted the expression of lipocalin (LCN) 2, accompanied by the reduction of C-X-C chemokine receptor type (CXCR) 4 and the increase of nuclear factor erythroid 2-related factor (NRF) 2 and activated extracellular signal-regulated kinase (ERK) 1/2 within thalamic astrocytes following chronic TH. In addition, the suppression of Oba to allodynia and ectopic activity of cortical neurons, as well as the promotion of Oba to phagocytosis of thalamic astrocytes to synapses, could be reversed by inhibiting LCN2, which was in line with the analgesic effect of adenovirus-mediated overexpression of astrocytic LCN2. Furthermore, neutralizing the macrophage migration inhibitory factor (MIF), the potential target of Oba, suppressed TH-induced allodynia, which was not further regulated by Oba treatment. These results collectively conclude that Oba promotes the phagocytotic function of thalamic astrocytes to synapses via elevating astrocyte LCN2. This process may be mediated by MIF-related signaling, including CXCR4, NRF2, and ERK1/2. The elimination of thalamic synapses obtunds nociceptive input and eventually alleviates TH-induced allodynia. Oba may represent a therapeutic candidate for thalamic pain and pain disorders caused by cerebral stroke.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281663","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":"Emerging Techniques for the Identification of Traditional Chinese Medicine-Derived Molecules Targeting Parkinson's Disease.","authors":"Yanzhuo Jin, Yurun Yang, Yiran Sun, George D Mellick, Yuanjun Sun, Mingming Xu","doi":"10.1021/acschemneuro.5c00127","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00127","url":null,"abstract":"<p><p>Parkinson's disease is a neurodegenerative disorder marked by the aggregation of α-synuclein and substantial loss of dopaminergic neurons. While numerous neuroprotective molecules targeting Parkinson's disease have been identified, challenges remain in optimizing the specificity, selectivity, and efficiency of these molecules. Traditional Chinese medicine has emerged as a bountiful source of natural compounds with diverse pharmacological activities, including inhibition of apoptosis or neuroinflammation, modulation of α-synuclein aggregation and clearance of α-synuclein aggregates. This review provides a comparative analysis of representative molecules derived from traditional Chinese medicine that have shown promise in advancing Parkinson's disease treatment, including tanshinones, paeoniflorin, and ginsenosides. Moreover, the review highlights the role of leading-edge analytical techniques, particularly mass spectrometry and magnetic beads, in identifying and characterizing bioactive compounds, streamlining the process of molecule screening, and offering a more efficient approach for drug discovery. By integrating traditional herbal knowledge with modern scientific techniques, this review seeks to offer researchers constructive information about the development of novel molecules with potential for Parkinson's disease treatment.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273650","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":"Therapeutic Role of l-Theanine in Mitigating Cognitive Dysfunction and Neuropathology in Scopolamine-Treated Mice.","authors":"Eman M Elbaz, Sherehan M Ibrahim, Eman Rashad, Noha A E Yasin, Heba R Ghaiad, Noha A Mehana","doi":"10.1021/acschemneuro.5c00351","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00351","url":null,"abstract":"<p><p>Memory decline is a prominent hallmark of Alzheimer's disease (AD). Scopolamine-induced amnesia is a pharmacological paradigm in AD research to model these cognitive insults. AD represents the most prevalent type of dementia among the elderly, depicted by impaired cognition and memory. AD pathogenesis is an interplay among cholinergic signaling disruption, neuroinflammation, and oxidative stress. Recently, autophagy modulation has been proven to display a beneficial effect against several diseases. l-Theanine (LTA), found in green tea, possesses neuroprotective, anti-inflammatory, antioxidant, and antiaging properties. Hence, this study investigated LTA's potential to alleviate AD symptoms, elaborating the role of autophagy. 45 mice were classified into five groups: the control, where animals received phosphate-buffered saline, while the other groups received scopolamine (Scop; 1 mg/kg; i.p.), inducing amnesia; then they were categorized as follows: group II represented the model one, group III was treated with donepezil (DON; 5 mg/kg; p.o.), while group IV was treated with LTA (20 mg/kg; p.o.), and group V received chloroquine (CQ; 10 mg/kg; p.o.), an autophagy blocker, followed by LTA. LTA stimulated AMP-activated protein kinase (AMPK), microtubule-associated protein-1 light chain-3II (LC3II), and beclin 1 but lowered phosphorylated levels of protein kinase B (p-AKT) and mammalian target of rapamycin (p-mTOR). Furthermore, LTA elevated the brain-derived neurotrophic factor (BDNF) and downregulated caspase-3 expression. Noteworthily, LTA increased glutathione and reduced malondialdehyde and tumor necrosis factor-alpha levels. In conclusion, LTA ameliorated histopathological changes, reduced amyloid-β, and enhanced learning and memory performance in novel object recognition, Y-maze, and Morris water maze. LTA boosted autophagy, promoted neuronal survival, and attenuated oxidative stress. LTA almost displayed similar effects to the DON group, while CQ abolished LTA-enhanced memory via blocking autophagy. Consequently, LTA-mediated autophagy represents a promising approach to alleviating Scop-induced amnesia in mice.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281664","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":"Altered Composition of Ceramides and Sphingomyelin Distinctly Modulates the Organizational Landscape and Microdomain Dynamics of Neuronal Plasma Membrane: A Computational Microscopy of Alzheimer's Brain.","authors":"Sruthi Peesapati, Sandipan Chakraborty","doi":"10.1021/acschemneuro.5c00261","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00261","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is one of the leading causes of death in the elderly population. Currently, there is no available therapy that can stop the disease progression. Situations are much worse due to a lack of a clear understanding of disease pathogenesis and the unavailability of an appropriate biomarker for early diagnosis. Higher ceramide levels were strongly linked to an increased risk of AD. However, the effect of increased ceramide concentration on the spatiotemporal organization and dynamics of neuronal membranes in diseased conditions is poorly understood. Based on the lipidomics data, we have modeled biologically relevant neuronal model membranes for healthy brain (HB) and diseased condition AD brain (ADB). The effects of the increase in ceramides and the lowering of sphingomyelin on the overall membrane organization, fluidity, stability, and dynamics of membrane microdomains have been investigated through extensive molecular dynamics (MD) simulations. Healthy neuronal membranes are less curved than the ADB. In ADB, cholesterols exhibit a higher local enrichment around cholesterol, but its enrichment decreases significantly around ceramide. In contrast, ceramides are enriched around themselves in the ADB. Enhancement in the ceramide content promotes cholesterol-sphingomyelin-enriched but ceramide-deficient microdomains. At the same time, ceramides tend to coalesce and form ceramide-enriched microdomains with a significantly longer residence time. The AD neuronal membrane has a higher number of highly stable ceramide-exclusive microdomains. Ceramide-enriched microdomains are known to enhance amyloidogenic processing. The study provides insight into the role of ceramides and sphingomyelins in AD disease pathogenesis and enhances the potential of lipid-based biomarkers for early detection.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264751","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}