ACS Chemical Neuroscience最新文献

{"title":"Unlocking Neuroinflammation: A Balanced Art for Therapeutics of Prion Disease.","authors":"Cao Chen, Xiaoping Dong","doi":"10.1021/acschemneuro.4c00871","DOIUrl":"10.1021/acschemneuro.4c00871","url":null,"abstract":"<p><p>Neuroinflammation plays a dual role in prion diseases, contributing both to the clearance of misfolded scrapie-like prion protein and to neuropathology through chronic activation of inflammatory pathways. Key mechanisms, including M-CSF/CSF1R signaling, NLRP3 inflammasome activation, and the Galectin-3/TREM2 axis, etc., highlight the complexity of targeting neuroinflammation for therapeutic intervention. Balancing the modulation of these pathways while preserving beneficial immune responses and maintaining blood-brain barrier integrity is critical for developing effective treatments.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"281-283"},"PeriodicalIF":4.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996027","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":"Biological Amyloids Chemically Damage DNA.","authors":"Istvan Horvath, Obed Akwasi Aning, Sriram Kk, Nikita Rehnberg, Srishti Chawla, Mikael Molin, Fredrik Westerlund, Pernilla Wittung-Stafshede","doi":"10.1021/acschemneuro.4c00461","DOIUrl":"10.1021/acschemneuro.4c00461","url":null,"abstract":"<p><p>Amyloid fibrils are protein polymers noncovalently assembled through β-strands arranged in a cross-β structure. Biological amyloids were considered chemically inert until we and others recently demonstrated their ability to catalyze chemical reactions in vitro. To further explore the functional repertoire of amyloids, we here probe if fibrils of α-synuclein (αS) display chemical reactivity toward DNA. We demonstrate that αS amyloids bind DNA at micromolar concentrations in vitro. Using the activity of DNA repair enzymes as proxy for damage, we unravel that DNA-amyloid interactions promote chemical modifications, such as single-strand nicks, to the DNA. Double-strand breaks are also evident based on nanochannel analysis of individual long DNA molecules. The amyloid fold is essential for the activity as no DNA chemical modification is detected with αS monomers. In a yeast cell model, there is increased DNA damage when αS is overexpressed. Chemical perturbation of DNA adds another chemical reaction to the set of activities emerging for biological amyloids. Since αS amyloids are also found in the nuclei of neuronal cells of Parkinson's disease (PD) patients, and increased DNA damage is a hallmark of PD, we propose that αS amyloids contribute to PD by direct chemical perturbation of DNA.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"355-364"},"PeriodicalIF":4.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941422","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":"Muscle Matters: Transforming Amyotrophic Lateral Sclerosis Diagnostics with Next-Gen Biosensors and Smart Detection","authors":"Saumitra Singh,&nbsp;Sameer Khan,&nbsp;Shina Khan,&nbsp;Osheen Ansari,&nbsp;Nitesh Malhotra,&nbsp;Sudheesh K. Shukla and Jagriti Narang*,&nbsp;","doi":"10.1021/acschemneuro.4c0066410.1021/acschemneuro.4c00664","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00664https://doi.org/10.1021/acschemneuro.4c00664","url":null,"abstract":"<p >Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily targets the motor system, causing patients’ speech and swallowing ability to rapidly deteriorate. Although ALS is usually classified into familial and sporadic forms, diagnosing it can be extremely difficult due to the absence of definitive biomarkers, often resulting in delays in diagnosis. Current diagnostic practices rely heavily on clinical assessments that indicate damage to both upper motor neurons (UMNs) and lower motor neurons (LMNs). This includes comprehensive physical examinations, electromyography (EMG) to assess neuromuscular function, and the exclusion of other similar conditions such as cervical spondylotic myelopathy, multifocal motor neuropathy, and Kennedy’s disease through appropriate diagnostic procedures. The urgent need for specific biomarkers is critical for timely diagnosis and therapeutic advancements in ALS management. While many recent developments in research have not yet translated into direct patient benefits, the recognition of ALS as a complex disease is beginning to influence clinical practice significantly. Optimal management strategies emphasize on symptom control and improving the quality of life for patients within a holistic healthcare framework. This review provides a comprehensive overview of ALS, delving into its pathophysiology, clinical symptoms, and the latest advancements in detection methods that utilize traditional approaches, innovative biosensors, and smart diagnostic technologies. It discusses various treatment options available for ALS while exploring future developments that may enhance patient screening and improve clinical outcomes. By integrating assessments into the underlying mechanisms of the disease with cutting-edge diagnostic approaches, this review aims to contribute meaningfully to ongoing efforts to optimize ALS management and therapeutic strategies, ultimately improving patient care and outcomes.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 4","pages":"563–587 563–587"},"PeriodicalIF":4.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435910","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":"Sapphire-Based Optrode for Low Noise Neural Recording and Optogenetic Manipulation","authors":"Yanyan Xu,&nbsp;Ben-Zheng Li,&nbsp;Xinlong Huang,&nbsp;Yuebo Liu,&nbsp;Zhiwen Liang,&nbsp;Xien Yang,&nbsp;Lizhang Lin,&nbsp;Liyang Wang,&nbsp;Yu Xia,&nbsp;Matthew Ridenour,&nbsp;Yujing Huang,&nbsp;Zhen Yuan,&nbsp;Achim Klug,&nbsp;Sio Hang Pun,&nbsp;Tim C. Lei and Baijun Zhang*,&nbsp;","doi":"10.1021/acschemneuro.4c0060210.1021/acschemneuro.4c00602","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00602https://doi.org/10.1021/acschemneuro.4c00602","url":null,"abstract":"<p >Electrophysiological recording of neurons in deep brain regions using optogenetic stimulation is a powerful method for understanding and regulating the role of complex neural activity in biological behavior and cognitive function. Optogenetic techniques have significantly advanced neuroscience research by enabling the optical manipulation of neural activities. Because of the significance of the technique, constant advancements in implantable optrodes that integrate optical stimulation with low-noise, large-scale electrophysiological recording are in demand to improve the spatiotemporal resolution for various experimental designs and future clinical applications. However, robust and easy-to-use neural optrodes that integrate neural recording arrays with high-intensity light emitting diodes (LEDs) are still lacking. Here, we propose a neural optrode based on Gallium Nitride (GaN) on sapphire technology, which integrates a high-intensity blue LED with a 5 × 2 recording array monolithically for simultaneous neural recording and optogenetic manipulation. To reduce the noise interference between the recording electrodes and the LED, which is in close physical proximity, three metal grounding interlayers were incorporated within the optrode, and their ability to reduce LED-induced artifacts during neural recording was confirmed through both electromagnetic simulations and experimental demonstrations. The capability of the sapphire optrode to record action potentials has been demonstrated by recording the firing of mitral/tuft cells in the olfactory bulbs of mice in vivo. Additionally, the elevation of action potential firing due to optogenetic stimulation observed using the sapphire probe in medial superior olive (MSO) neurons of the gerbil auditory brainstem confirms the capability of this sapphire optrode to precisely access neural activities in deep brain regions under complex experimental designs.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 4","pages":"628–641 628–641"},"PeriodicalIF":4.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435905","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":"Computational Study of the Activation Mechanism of Wild-Type Parkin and Its Clinically Relevant Mutant.","authors":"Zeynep Nur Cinviz, Ozge Sensoy","doi":"10.1021/acschemneuro.4c00630","DOIUrl":"10.1021/acschemneuro.4c00630","url":null,"abstract":"<p><p>Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. It impairs the control of movement and balance. Parkin mutations worsen the symptoms in sporadic cases and cause the early onset of the disease. Therefore, recent efforts have focused on the rescue of defective parkin by engineered proteins or small-molecule activators to enhance parkin activation. These attempts require holistic understanding of the multistep activation mechanism and molecular effects of disease-associated mutations. Hereby, we provided a comprehensive analysis of the activation mechanism of parkin and a clinically relevant mutant, parkin^S167N, using molecular dynamics simulations based on the following crystal structures: (1) parkin, (2) parkin/pUb (phosphorylated Ubiquitin), (3) pparkin/pUb, and (4) pparkin/pUb/UbcH7-Ub. Each of these represents an individual step in the activation process. We showed that the mutation impacted the dynamics of not only the RING0 domain, where it is localized, but also the RING2, Ubl, and IBR domains. We identified residues participating in the allosteric interaction network involved in parkin activation. Some of them are mutated in PD-associated parkin variants. The RING0 domain provides a binding interface with various proteins, so understanding problems associated with the mutation paves the way to the discovery of effective engineered proteins or small molecules that activate mutant parkin.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"417-427"},"PeriodicalIF":4.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044866","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":"Elevated BACE1 and IFNγ+ T Cells in Patients with Cognitive Impairment and the 5xFAD Mouse Model.","authors":"Yaxi Zhan, Zuolong Chen, Shuxin Zheng, Linbin Dai, Wei Zhang, Yumeng Dai, Feng Gao, Yong Shen, Weiwei Zhang","doi":"10.1021/acschemneuro.4c00565","DOIUrl":"10.1021/acschemneuro.4c00565","url":null,"abstract":"<p><p>The dysregulation of T cell differentiation was associated with cognitive impairment. Recently, the peripheric β-secretase (BACE1) has been suggested as a regulator of T cell differentiation, which was increased in both cognitive impairment (CI) and type 2 diabetes mellitus (T2DM) in CI patients. However, the relationship between T cell dysfunction and CI remains unclear. To address this question, we measured T cell subtypes and BACE1 enzyme activity in a clinical cohort and 5xFAD mice. We found that both IFNγ+ Th1 and Tc1 cells were increased in the CI and T2DM-CI groups, which were associated with worsening cognitive function. The elevated IFNγ + Th1 and Tc1 cells were also observed in 8-month-old 5xFAD mice. The elevated BACE1-mediated INSR cleavage was associated with increased IFNγ + Th1 and Tc1 cells. These findings demonstrate the potential role of elevated BACE1 in IFNγ+ T cells and CI.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"384-392"},"PeriodicalIF":4.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11804866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981958","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":"Targeted Metabolomics for the Analysis of <i>p-</i>Cresol in Mouse Brain: Impact of Biological Sex and Strain.","authors":"Laura Bertarini, Federico Imbeni, Antonietta Vilella, Silvia Alboni, Federica Pellati","doi":"10.1021/acschemneuro.4c00698","DOIUrl":"10.1021/acschemneuro.4c00698","url":null,"abstract":"<p><p><i>p</i>-Cresol, an environmental contaminant and endogenous metabolite derived primarily from the conversion of l-tyrosine by intestinal microflora, is gaining increasing attention, due to its potential impact on human health. Recent studies have highlighted elevated levels of <i>p</i>-cresol and its metabolites, including <i>p</i>-cresyl sulfate and <i>p</i>-cresyl glucuronide, in various populations, suggesting a correlation with neurodevelopmental and neurodegenerative conditions. While the role of this compound as a uremic toxin is well established, its presence and concentration within the central nervous system (CNS) remain largely unexplored. To address this gap, an high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method was optimized and validated for the first time in this work for the targeted metabolomics of <i>p</i>-cresol in brain tissues. This method enabled the quantification of this compound in different brain areas of adult male and female C57BL/6J mice and in the cortex of various mouse strains, including CD-1 and the idiopathic autism model BTBR T⁺Itpr3^tf/J. Additionally, preliminary analyses of human cortex samples confirmed the presence of <i>p</i>-cresol, suggesting its relevance in human brain health. Moreover, metabolomic analyses have further explored the correlations between <i>p</i>-cresol and neurotransmitters, with a particular focus on dopaminergic and noradrenergic pathways. These findings pave the way for understanding the potential impact of <i>p</i>-cresol on neurochemical networks and its implications for neurodevelopmental and neurodegenerative disorders.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"452-461"},"PeriodicalIF":4.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996026","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":"Serotonergic Mechanisms in Proteinoid-Based Protocells.","authors":"Panagiotis Mougkogiannis, Andrew Adamatzky","doi":"10.1021/acschemneuro.4c00801","DOIUrl":"10.1021/acschemneuro.4c00801","url":null,"abstract":"<p><p>This study examines the effects of incorporating serotonin (5-HT) into proteinoid microspheres. It looks at the microspheres' structure and electrochemical properties. Proteinoid-serotonin assemblies have better symmetry and membrane organization than pristine proteinoids. Cyclic voltammetry shows a big boost in electron transfer. This is proven by a smaller peak separation and higher electrochemical efficiency. SEM imaging shows a distinct core-shell structure and uniform density. This suggests ordered molecular assembly. These findings show that serotonin changes proteinoid self-assembly. It creates structured systems with better electron transfer pathways. The serotonin-modified proto-neurons show new properties. They give insights into early cellular organization and signaling. This helps us understand prebiotic information processing systems.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"519-542"},"PeriodicalIF":4.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996006","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":"Exosomal PINK1 from Human Umbilical Cord Mesenchymal Stem Cells Attenuates Neurological Deficits and Inflammatory Responses after Intracerebral Hemorrhage in Mice","authors":"Jianliang Li,&nbsp;Liang Yang,&nbsp;Lin Zhao and Jingchen Li*,&nbsp;","doi":"10.1021/acschemneuro.4c0057510.1021/acschemneuro.4c00575","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00575https://doi.org/10.1021/acschemneuro.4c00575","url":null,"abstract":"<p >This study investigated the therapeutic potential of exosomes from human umbilical cord mesenchymal stem cells (huMSCs), focusing on PTEN-induced kinase 1 (PINK1) and its impact on exosome efficacy. Postmodification, exosomes were administered to a murine model of intracranial hemorrhage (ICH). Assessments included brain edema, neurological function, anxiety-like behaviors, inflammatory responses, and microglial polarization. We observed that administration of exosomes from control huMSCs significantly reduced brain water content, indicating a reduction in brain edema, as quantitatively assessed through water content analysis. Neurological function, evaluated using a standard scoring system, showed marked improvement in animals treated with control exosomes compared with those receiving PINK1-deficient exosomes, highlighting the importance of PINK1 in mediating neurological recovery. Additionally, control exosomes substantially decreased anxiety-like behaviors in the Open Field Test, demonstrated by reduced immobility times and increased exploratory behavior. Inflammatory response assessments showed a favorable shift with decreased levels of pro-inflammatory cytokines (MCP-1, IL-1β, TNF-α) and increased levels of the anti-inflammatory cytokine IL-10 in the exosome-treated groups. Furthermore, analysis of microglial polarization revealed a shift toward the anti-inflammatory M2 phenotype, evidenced by decreased M1 markers (Cd86, Iba1) and increased M2 markers (Arg1, Cd206) in the control exosome-treated group. Taken together, we found that PINK1-deficient exosomes showed reduced therapeutic efficacy in ICH treatment compared with the exosomes with normal PINK1 expression. Our findings underscore the critical role of PINK1 in enhancing the therapeutic potential of huMSC-derived exosomes in ICH treatment.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 4","pages":"619–627 619–627"},"PeriodicalIF":4.1,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436110","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":"Quantitative Analysis of Neuropeptide Y (NPY) and C-Terminal Glycine-Extended NPY by Mass Spectrometry and Their Localization in the Developing and Sexual Adult Mouse Brains","authors":"Tohru Yamagaki*,&nbsp;Tomohiro Osugi,&nbsp;Yohei Shinmyo,&nbsp;Hiroshi Kawasaki and Honoo Satake,&nbsp;","doi":"10.1021/acschemneuro.4c0054510.1021/acschemneuro.4c00545","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00545https://doi.org/10.1021/acschemneuro.4c00545","url":null,"abstract":"<p >Neuropeptide Y (NPY), a central stimulator of food intake and an energy balance controlling hormone, was quantitatively analyzed in developing brains at birth using microflow liquid chromatography (LC) and triple-quadrupole tandem mass spectrometry (MS/MS). We detected and identified endogenous C-terminal glycine-extended NPY (NPY-Gly 1–37) first, an intermediate of NPY before amidation in the mouse brain using high-resolution Fourier-transform Orbitrap MS and MS/MS. NPY-Gly was present in the fetal brain (E16) at almost the same levels as NPY of 1.92 pmol/g-brain tissue. After birth, NPY in postnatal 2-day brains (P2) was elevated drastically at 11.02 pmol/g-brain (<i>p</i> &lt; 0.05 vs E16) and remained at a high level for the first 10 postnatal days, an important period for the formation of the NPY neural circuit in the brain. Immunohistochemistry unexpectedly showed that the localizations of NPY and NPY-Gly in the hypothalamus were completely different: NPY was localized in the arcuate nucleus, whereas NPY-Gly was already located at pars tuberalis during brain development from a fetus to a neonate to a sexual adult.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 4","pages":"588–594 588–594"},"PeriodicalIF":4.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00545","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436065","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}