ACS Chemical Neuroscience最新文献

{"title":"CIRP: New Horizons for CNS Injury Biomarkers and Therapy","authors":"Na Lv,&nbsp;Hao Tian,&nbsp;Qiuyan Hao,&nbsp;Fengtang Yang,&nbsp;Hui Zhen,&nbsp;Zhonghong Cao","doi":"10.1021/acschemneuro.6c00414","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00414","url":null,"abstract":"<p>Cold-inducibleRNA-binding protein (CIRP) is a stress-responseprotein that protects cells under conditions of low temperature andother stresses. The expression of CIRP is induced by various stressors.CIRP regulates gene expression through complex, multi-layered mechanismsand plays a central role in physiological and pathological processes,including cell proliferation, apoptosis, inflammatory responses, andcircadian rhythms. In central nervous system (CNS) injuries, CIRPexhibits a dual role. Intracellular CIRP has a neuroprotective function.In contrast, when released into the extracellular space as eCIRP,it acts as a damage-associated molecular pattern (DAMP) that exacerbatesneuroinflammation. Serum levels of eCIRP are significantly elevatedin patients with CNS injuries, such as acute ischemic stroke and intracerebralhemorrhage, suggesting its potential as a biomarker for diagnosisand prognosis. Furthermore, targeting the eCIRP signaling pathwayhas shown significant therapeutic effects in various models of neurologicalinjury. Strategies include using inhibitory peptides like C23 andM3, as well as microRNA-based approaches. Here, we systematicallyreview the molecular characteristics, expression regulation, and biologicalfunctions of CIRP, with a focus on its neuroprotective role, biomarkerpotential, and therapeutic targeting in CNS injuries.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 20","pages":"3408–3420"},"PeriodicalIF":4.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221993","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":"Development of NanoBRET Cellular Target Engagement Assays in Primary Neurons for Activating Mutants of p21-Activated Kinase 1","authors":"Jacob L. Capener,&nbsp;Abdiel Badillo-Martinez,&nbsp;Bassel Awada,&nbsp;Zachary W. Davis-Gilbert,&nbsp;Thomas W. Kramer,&nbsp;Cameron S. Blair,&nbsp;Frances M. Bashore,&nbsp;Hassan Al-Ali,&nbsp;Alison D. Axtman","doi":"10.1021/acschemneuro.6c00326","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00326","url":null,"abstract":"<p>The p21-activatedkinases (PAKs) are a group of serine-threoninekinases central to multiple signaling pathways that govern cell survivaland proliferation. Aberrant activity of PAK1, the most well characterizedmember of the PAK family, drives progression of several malignanciesand brain disorders, including Alzheimer’s disease and neurodevelopmentaldisorders. Despite growing interest in PAK1 as a drug target for thesediseases, there is no assay to evaluate the intracellular target engagementof PAK1 inhibitors. To address this need, we developed first-in-classNanoBRET assays for wild-type PAK1 and a neurodevelopmental disorder-causinggain-of-function PAK1 mutant. Furthermore, we executed our novel PAK1NanoBRET assay to evaluate target engagement of PAK1 inhibitors inprimary hippocampal neurons. To the best of our knowledge, this isthe first demonstration of a NanoBRET cellular target engagement assayin primary neurons, thereby increasing the relevance of our work byconfirming PAK1 inhibitor binding to the aberrant form of the proteinin cerebral cells.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 20","pages":"3441–3452"},"PeriodicalIF":4.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149222022","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":"Serotonin Neurobiology and Artificial Intelligence-Driven Biomarker Detection in Affective Disorders: A Comprehensive Review","authors":"Madiha Farooqui,&nbsp;Minha Fatima,&nbsp;Sameer Khan,&nbsp;Saumitra Singh,&nbsp;Furqan Choudhary,&nbsp;Tabinda Farooq,&nbsp;Anish Murtaja Alam Khan,&nbsp;Maryam Sarwat,&nbsp;Humaira Farooqi","doi":"10.1021/acschemneuro.6c00406","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00406","url":null,"abstract":"<p>Affective disorders, including major depressive disorder(MDD)and generalized anxiety disorder (GAD), impose a major global healthburden because of their high prevalence, early onset, disability,and substantial social and economic impacts. Diagnosis remains challengingbecause it relies largely on subjective clinical assessment and symptom-basedcriteria, which often delay recognition and contribute to heterogeneoustreatment response. Serotonin (5-hydroxytryptamine, 5-HT) has longbeen central to the understanding of these disorders, but the classicalserotonin hypothesis has evolved into a broader systems-level frameworkin which serotonergic dysfunction is linked with neurotransmission,receptor signaling, transporter regulation, neuroplasticity, endocrinebalance, immune modulation, circadian rhythm control, and gut-braincommunication. Serotonin biosynthesis, metabolism, and compartmentalizationare tightly regulated, and variation in the serotonin transporterand related pathways influences vulnerability to disease, symptomexpression, and response to therapy. Although serotonin-targeted pharmacotherapyremains foundational, its delayed and variable clinical effects highlightthe need for objective biomarkers and more-precise monitoring strategies.This Review gives a comprehensive overview of serotonin neurobiologyin affective disorders and the therapeutic implications of serotonergicdysregulation. It discusses the current understanding of serotoninsynthesis, receptor heterogeneity, transporter function, and broadersystem interactions that shape mood, stress responsivity, and treatmentoutcomes. The Review also examines the growing role of artificialintelligence in psychiatric biomarker discovery, including machinelearning and deep learning approaches applied to neuroimaging, electrophysiology,physiological signals, and language-based data for improved diagnosisand prediction of antidepressant responses. In addition, emergingserotonin-specific biosensors are discussed as promising tools forreal-time, noninvasive neurochemical monitoring. By integrating mechanisticinsights into serotonin biology with AI-based analytics and biosensingtechnologies, this Review highlights a pathway toward more objective,personalized, and effective management of affective disorders.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 20","pages":"3388–3407"},"PeriodicalIF":4.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221888","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":"Indolizine-Based Small-Molecule Fluorescent Probes for Ex Vivo Imaging of Amyloid-β Plaques","authors":"InWook Park,&nbsp;Kyeonghwan Kim,&nbsp;Sunhee Lee,&nbsp;Wonbin Seo,&nbsp;Hye Yun Kim,&nbsp;Ikyon Kim,&nbsp;YoungSoo Kim","doi":"10.1021/acschemneuro.6c00366","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00366","url":null,"abstract":"<p>Fluorescenceprobes for visualizing amyloid-β (Aβ)plaques are important tools in Alzheimer’s disease (AD) research.We synthesized a library of 49 indolizine derivatives using a modularsynthetic approach and evaluated their fluorescence labeling behaviordirectly in <em>ex vivo</em> brain tissue sections from 5XFADtransgenic mice. Through an <em>ex vivo</em> tissue-basedscreening workflow using anti-Aβ antibody 6E10 as a referencestandard for plaque-containing regions, five hit compounds (YIZ-20,YIZ-32, YIZ-36, YIZ-45, and YIZ-47) displaying plaque-associated fluorescencepatterns were identified. Costaining experiments demonstrated spatialcorrespondence between probe fluorescence and antibody-defined plaqueregions. Spectral analysis showed that the selected YIZ probes exhibitedemission profiles with somewhat reduced overlap with the Hoechst 33342channel compared with thioflavin S (ThS), providing a modest but practicaladvantage for multichannel imaging applications. These findings highlightthe utility of <em>ex vivo</em> tissue-based screening forfluorescent-probe discovery and establish indolizine as a promisingscaffold for the development of complementary fluorescence imagingtools for AD-related <em>ex vivo</em> tissue studies.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 20","pages":"3431–3440"},"PeriodicalIF":4.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221991","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":"Correction to “Negative Allosteric Modulator of mGluR1 Improves Long-Term Neurologic Deficits after Experimental Subarachnoid Hemorrhage”","authors":"Hong-Bin Wang,&nbsp;Wei-qi Wang,&nbsp;Qing-Jian Wu,&nbsp;Ya-jun Hou,&nbsp;Han-xia Li,&nbsp;Hui-juan Yang,&nbsp;Ming-feng Yang,&nbsp;Bao-liang Sun,&nbsp;Zong-yong Zhang","doi":"10.1021/acschemneuro.6c00703","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00703","url":null,"abstract":"","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 20","pages":"3453–3454"},"PeriodicalIF":4.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221953","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":"Correction to “Discovery of VU6077564: A Selective M1 Antagonist that Promotes Neurite Outgrowth in Adult Sensory Neurons”","authors":"Tomayo I. Berida,&nbsp;Cayden J. Dodd,&nbsp;Joshua C. Wilkinson,&nbsp;Darrell R. Smith,&nbsp;Sichen Chang,&nbsp;Christopher C. Presley,&nbsp;Li Peng,&nbsp;Snehal Sant,&nbsp;Srinivasan Krishnan,&nbsp;Irene Zagol-Ikapitte,&nbsp;Katherine J. Watson,&nbsp;Analisa Thompson Gray,&nbsp;Alice L. Rodriguez,&nbsp;Hyekyung P. Cho,&nbsp;Carrie K. Jones,&nbsp;Olivier Boutaud,&nbsp;Colleen M. Niswender,&nbsp;Darren W. Engers,&nbsp;Paul Fernyhough,&nbsp;Craig W. Lindsley,&nbsp;Elizabeth S. Childress","doi":"10.1021/acschemneuro.6c00717","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00717","url":null,"abstract":"","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 20","pages":"3455–3457"},"PeriodicalIF":4.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149222085","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":"Aβ-42 Side Chain Deamidation at Q15 or N27 Modulates Protein Aggregation and Alters Microglial Cytokines and CD68","authors":"Martin N. Griffin,&nbsp;Daniel M. Dinakarapandian,&nbsp;Chenxing Li,&nbsp;Pranay Ramaswamy,&nbsp;Sia J. Saheba,&nbsp;Janie Lee,&nbsp;Tarunya Rao Sudarshan,&nbsp;Maria Sajimon,&nbsp;Christopher J. Wheeler,&nbsp;Jevgenij A. Raskatov,&nbsp;Anant K. Paravastu,&nbsp;Levi B. Wood","doi":"10.1021/acschemneuro.6c00024","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00024","url":null,"abstract":"<p>The progressive aggregation of amyloid beta (Aβ)monomersinto oligomers is a critical factor in Alzheimer’s disease(AD) pathogenesis. Although mutated forms of Aβ have been shownto display altered aggregation dynamics, the specific effects of deamidatedAβ on microglial function remain understudied. Our researchgroup previously found that the deamidated variant Aβ-42-N27Dmodified Aβ aggregation, reduced neurotoxicity, and reducedmicroglial reactivity, but the impact of Aβ-42 side chain deamidationin general on such parameters remained unclear. Here, we expandedon our prior work by investigating how two site-specific Aβ-42mutations (Q15E &amp; N27D), where neutral amide side chains are replacedwith negatively charged carboxylic acids, affect aggregation and microglialimmune response using a mouse microglial cell line. Size exclusionchromatography, Thioflavin T fluorescence, circular dichroism, anddynamic light scattering revealed that Aβ-42-Q15E and Aβ-42-N27Dexhibit reduced aggregation compared to Aβ-42 wild type (WT).Multiplexed analysis of 8 microglial cytokines secreted into the culturemedium revealed that Aβ-42-Q15E and Aβ-42-N27D decreasethe expression of inflammatory cytokines such as IL-6, IP-10, andMIP-1α relative to Aβ-42-WT. Immunocytochemistry revealedthat Aβ-42-Q15E and Aβ-42-N27D decrease CD68 expressionand intracellular Aβ labeling relative to Aβ-42-WT. Thesefindings demonstrate that deamidation significantly alters Aβ-42aggregation and microglial activation, suggesting structural modificationsto Aβ-42 modulate inflammatory signaling in AD. This work providesa foundation for future studies on Aβ-42 post-translationalmodifications as potential therapeutic targets in AD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 20","pages":"3421–3430"},"PeriodicalIF":4.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221887","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":"Guanidine-Functionalized Aminoglycosides Enable miR-7a Delivery to Attenuate Neuroferroptosis","authors":"Milind Kumar Anand,&nbsp;Pardhasaradhi Satha,&nbsp;Hariharan Moorthy,&nbsp;Madhu Ramesh,&nbsp;Sabyasachi Mandal,&nbsp;Thimmaiah Govindaraju","doi":"10.1021/acschemneuro.6c00389","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00389","url":null,"abstract":"<p>Ferroptosis is an iron-dependent form of regulated celldeath drivenby lipid peroxidation and increasingly recognized as a key contributorto neurodegeneration (neuroferroptosis). Current pharmacological approachesprimarily target downstream ferroptotic events and do not addressupstream epigenetic regulation. MicroRNA (miRNA)-mediated modulationrepresents a potential strategy to overcome this limitation, whileits application is hindered by the lack of delivery vectors that combineefficient nucleic acid delivery with physiological compatibility.In this study, guanidinium-functionalized aminoglycosides (GAs) areinvestigated as a natural product-derived small-molecule carrier formiRNA delivery. GAs form stable nanocomplexes with miR-7a, an epigeneticregulator of neuroferroptosis, through multivalent guanidinium-mediatedinteractions, enabling efficient cellular uptake. Among the moleculesevaluated, neomycin G (NEO G) exhibited enhanced miRNA binding, improvedintracellular delivery, and functional activity under viscosity conditionsclosely recapitulating the extracellular milieu, wherein conventionaldelivery vectors typically display reduced efficacy. Delivery of miR-7amimic using NEO G results in effective downregulation of Krüppel-likefactor 4 (Klf4), a transcription factor implicated in neuroferroptosis,and confers significant neuroprotection via modulation of the miR-7a-Klf4axis. These findings identify GAs as a biocompatible and effectiveplatform for miRNA delivery and highlight their potential utilityin miRNA therapeutic strategies targeting neuroferroptosis.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 19","pages":"3370–3387"},"PeriodicalIF":4.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149093609","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":"Cyclic Peptides Target CAPON and Modulate Cellular Responses under Alzheimer’s Disease-Relevant Stress","authors":"Ashraf Abdo,&nbsp;Shaoren Yuan,&nbsp;Katarzyna Kuncewicz,&nbsp;Jisong Mo,&nbsp;Hongliang Duan,&nbsp;Moustafa T. Gabr","doi":"10.1021/acschemneuro.6c00345","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00345","url":null,"abstract":"<p>CAPON (NOS1AP) is an adaptor protein involved in neuronalnitricoxide synthase (nNOS) signaling and has been implicated in Alzheimer’sdisease (AD), excitotoxicity, and tau-associated neurodegeneration.Here, we report the identification of cyclic peptide ligands targetingCAPON using phage display screening of a disulfide-constrained peptidelibrary. Phage enrichment, ELISA validation, microscale thermophoresis(MST), and biolayer interferometry (BLI) identified CAP1 as the leadpeptide, exhibiting low micromolar binding affinity toward CAPON.Computational studies further supported stable CAPON-CAP1 interactionsthrough complementary hydrophobic and electrostatic contacts. Functionally,CAP1 attenuated Aβ42-induced neuronal toxicity, suppressed NMDA-drivennitric oxide production, and reduced AT8 immunoreactivity under tau-stressconditions in neuronal models. In addition, CAP1 demonstrated favorablepreliminary pharmacokinetic properties, including good aqueous solubility,plasma stability, and measurable membrane permeability. Collectively,these findings establish the first cyclic peptide ligands targetingCAPON and identify CAP1 as a promising scaffold for the modulationof CAPON-dependent neurodegenerative signaling.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 19","pages":"3360–3369"},"PeriodicalIF":4.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124779","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":"Targeting the Zinc Metalloproteinase Superfamily in the CNS: Medicinal Chemistry Strategies To Optimize Selectivity, Pharmacokinetics, and Blood–Brain Barrier Permeability","authors":"Yuki Nagashima","doi":"10.1021/acschemneuro.6c00496","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00496","url":null,"abstract":"<p>The zinc metalloproteinase superfamily [matrix metalloproteinases(MMPs), a disintegrin and metalloproteinases (ADAMs), and ADAMs withthrombospondin motifs (ADAMTSs)] represents a high-value yet elusivetherapeutic target for peripheral disorders and central nervous system(CNS) pathologies. Historically, active-site-centric drug discoveryusing potent zinc-binding groups (ZBGs) has achieved subnanomolarpotency but suffered from severe cross-reactivity and poor pharmacokinetics,leading to widespread clinical failures. In particular, medicinalchemistry must simultaneously optimize enzyme selectivity, metabolicstability, and blood–brain barrier permeability to revitalizethis target class for the highly restricted CNS chemical space. Thiswork deconstructs the structural evolution of small-molecule inhibitorsfrom a rigorous medicinal chemistry perspective. Additionally, wehighlight the emerging paradigm of leveraging DNA-encoded chemicallibraries (DEL) to efficiently select basic, non-ZBG scaffolds thatbypass classical chelation pitfalls. Furthermore, through <em>in silico</em> profiling and CNS multiparameter optimization(CNS MPO) scoring, we demonstrate how targeted structural truncationcan successfully refine initially oversized DEL hits into highly optimized,CNS-compatible templates. Finally, this review provides a technology-drivenroadmap for navigating multiparameter optimization to achieve CNS-targetedmetalloproteinase drug discovery.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 19","pages":"3318–3333"},"PeriodicalIF":4.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124816","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}