ACS Chemical Neuroscience最新文献

{"title":"A High-Affinity NIR Fluorescent Probe for Aβ Oligomers Enables Theranostics Through Disrupting Membrane Interaction and Aggregation","authors":"Min Yang,&nbsp;Yuhan Wang,&nbsp;Jianhua Deng,&nbsp;Qinyue Wu,&nbsp;Zhangdong Wang,&nbsp;Qingguo Meng*,&nbsp;Peng Wang* and Jing Yang*,&nbsp;","doi":"10.1021/acschemneuro.6c00058","DOIUrl":"10.1021/acschemneuro.6c00058","url":null,"abstract":"<p >Amyloid-β (Aβ) oligomers serve as pivotal biomarkers and therapeutic targets in Alzheimer’s disease (AD) due to their early emergence in pathogenesis and high level of neurotoxicity. In this work, we introduce a class of D–π–A amphiphilic fluorescent probes engineered for simultaneous detection and therapeutic modulation of Aβ oligomers. The lead compound, API-QB, exhibits a near-infrared (NIR) wavelength upon interaction with Aβ oligomers and demonstrates high selectivity and sensitivity toward Aβ oligomers in both solution and simulated brain environments. Importantly, API-QB is able to inhibit Aβ aggregation by interacting with oligomers. Furthermore, probe API-QB can reduce the toxicity of Aβ oligomers by inhibiting the interaction between oligomers and cell membranes and suppressing the production of reactive oxygen species generated by Aβ oligomers. Therefore, probe API-QB, which features NIR emission at 720 nm, a <i>K</i>_d of 6.38 nM, and a 47-fold fluorescence enhancement upon binding to Aβ oligomers, represents an attractive multifunctional candidate for integrated diagnostic imaging and therapeutic intervention in AD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 13","pages":"2486–2493"},"PeriodicalIF":4.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148255818","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":"Short- and Long-Acting Psychedelics: Structure–Activity Relationships, Pharmacology, and Implications for Neuropsychiatric Therapeutics","authors":"Anoushka Bhat,&nbsp;Elmira Zolali,&nbsp;Mahfuz A. Sakib,&nbsp;Mohammad Rahimian,&nbsp;Lance R. McMahon,&nbsp;Nadezhda German* and Samuel Obeng*,&nbsp;","doi":"10.1021/acschemneuro.6c00202","DOIUrl":"10.1021/acschemneuro.6c00202","url":null,"abstract":"<p >Psychedelics have re-emerged as promising therapeutics for neuropsychiatric disorders, including depression, anxiety, post-traumatic stress disorder, and substance use disorders. While their beneficial effects are largely attributed to serotonin 2A (5-HT2A) receptor activation, psychedelics exhibit substantial diversity in chemical structure, receptor binding kinetics, metabolism, and duration of action. These differences underpin the distinction between short-acting psychedelics like <i>N,N</i>-dimethyltryptamine (DMT) and 5-methoxy-DMT, and long-acting compounds like lysergic acid diethylamide (LSD) and mescaline. Short-acting psychedelics may offer advantages in clinical settings where brief therapeutic sessions are preferred, while long-acting agents may be relatively more effective for clinical outcomes. This review highlights the chemistry, structure–activity relationships, and pharmacology of both short- and long-acting psychedelics. We examine key functional group modifications that influence receptor binding affinity, efficacy, and duration. By integrating insights from synthetic chemistry, pharmacology, and clinical effects, this review provides a framework for rational psychedelic drug development aimed at producing next-generation antidepressants, anxiolytics, and substance use disorder treatments with controlled and predictable clinical effects.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 12","pages":"2278–2301"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.6c00202","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148196423","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":"Iron Oxide Nanoparticles for Modulating Reactive Oxygen Species: Synthesis, Properties, and Therapeutic Applications in Disease Treatment","authors":"Yi-Bo Yuan,&nbsp;Miao-Miao Yin*,&nbsp;Meng-Kang Jiang,&nbsp;Na Zhang,&nbsp;Zhi-Yu Zuo and Yan-Jun Hu*,&nbsp;","doi":"10.1021/acschemneuro.5c00817","DOIUrl":"10.1021/acschemneuro.5c00817","url":null,"abstract":"<p >Despite substantial advances in modern medicine, neurodegenerative diseases, chronic disorders, and cancers remain major clinical challenges in which dysregulated reactive oxygen species (ROS) play a critical role. Iron oxide nanoparticles (IONPs), because of their unique physicochemical properties, have emerged as promising metal oxide nanomaterials for biomedical applications, particularly in regulating intracellular ROS levels. Although extensive studies have investigated IONPs in biomedicine, a systematic review focusing on their therapeutic roles has not been conducted. In this review, we summarize representative synthesis strategies and key properties of IONPs and highlight their therapeutic applications based on ROS scavenging, ROS generation, and other related mechanisms. In addition, safety issues, mechanistic insights, and prospects for clinical translation are discussed, aiming to provide a comprehensive framework to guide future research and accelerate clinical development of IONP-based therapies.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 12","pages":"2238–2261"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148196464","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":"PET Molecular Probes for Neuroinflammation in Neurodegenerative Diseases: Progress and Prospects","authors":"Hongjun Jin*,&nbsp;","doi":"10.1021/acschemneuro.6c00338","DOIUrl":"10.1021/acschemneuro.6c00338","url":null,"abstract":"<p >Neuroinflammation is a central pathological process underlying neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis. Positron emission tomography (PET) molecular probes now enable the noninvasive, quantitative visualization of neuroinflammatory processes in the living brain. This review surveys recent advances in PET probes targeting microglial activation markers─including the 18 kDa translocator protein (TSPO), the purinergic P2X7 receptor (P2X7R), colony-stimulating factor 1 receptor (CSF1R), and sphingosine-1-phosphate receptor 1 (S1PR1)─as well as astrocyte reactivity markers such as monoamine oxidase B (MAO-B) and imidazoline-2 binding sites (I2BS). I discuss the evolution from first-generation TSPO ligands to polymorphism-insensitive third-generation tracers, highlight emerging targets beyond TSPO, and evaluate the translational value of these probes for early diagnosis, disease staging, treatment monitoring, and drug development. Current challenges-including limited cellular specificity, genetic polymorphism effects, quantification difficulties, and clinical accessibility barriers─are analyzed alongside promising solutions. Integrating neuroinflammation PET into multimodal biomarker frameworks will be essential for advancing precision medicine in neurodegenerative diseases.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 12","pages":"2229–2237"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148196472","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 Transporter Blockade Reduces the Psychedelic-Like Effects of 4-Methoxy-N-methyl-N-isopropyltryptamine and Related Analogs","authors":"Grant C. Glatfelter*,&nbsp;Serena S. Schalk,&nbsp;Donna Walther,&nbsp;Alexander D. Maitland,&nbsp;Nicholas R. Gonzalez,&nbsp;John S. Partilla,&nbsp;Nicholas A. Anas,&nbsp;Andrew R. Chadeayne,&nbsp;Marilyn Naeem,&nbsp;David R. Manke,&nbsp;John D. McCorvy and Michael H. Baumann,&nbsp;","doi":"10.1021/acschemneuro.6c00083","DOIUrl":"10.1021/acschemneuro.6c00083","url":null,"abstract":"<p >Tryptamine psychedelics induce psychoactive effects via agonist actions at serotonin 2A receptors (5-HT_2A), but the compounds are generally nonselective. 4-Methoxy-<i>N</i>-methyl-<i>N</i>-isopropyltryptamine (4-MeO-MiPT) is a 5-HT_2A agonist which also blocks the 5-HT transporter (SERT) and has blunted visual and other psychedelic effects in humans. Here, we compared the pharmacology of 4-MeO-MiPT, its 4-hydroxy derivative (4-HO-MiPT), and related analogs with <i>N-</i>alkyl or 4-alkoxy variations. We hypothesized that compounds with more potent SERT uptake inhibition would display reduced 5-HT_2A-mediated psychedelic-like effects in the mouse head twitch response (HTR) model. <i>In vitro</i> target profiling revealed potent and efficacious 5-HT receptor activities for most of the compounds, including 5-HT_2A receptor agonism (EC₅₀ = 10–118 nM, <i>E</i>_max = 72–97% 5-HT). Importantly, 4-MeO-MiPT and its <i>N</i>,<i>N</i>-diisopropyl (4-MeO-DiPT) and <i>N</i>-methyl-<i>N</i>-cyclopropyl (4-MeO-McPT) analogs displayed more potent uptake inhibition at SERT (IC₅₀ = 17–107 nM) than their 4-OH counterparts (IC₅₀ = 280–423 nM). Studies administering the drugs subcutaneously to C57BL/6J mice revealed that 4-HO- and 4-MeO-MiPT (0.03–30 mg/kg) had similar potencies for inducing HTRs (ED₅₀ = 0.75 vs 0.97 mg/kg), but 4-MeO-MiPT had reduced efficacy (<i>E</i>_max = 77 vs 34 HTRs/30 min). A similar trend for decreased HTRs was observed for 4-MeO-DiPT and 4-MeO-McPT. Pretreatment with the SERT inhibitor fluoxetine (10 mg/kg) prior to 4-HO-MiPT, 4-HO-DiPT, or 4-HO-McPT reduced the maximal number of HTRs to levels observed for their respective 4-MeO analogs. Overall, our data indicate that 4-MeO-MiPT interacts with 5-HT_2A and other 5-HT receptors, but the drug also inhibits SERT to reduce the efficacy of psychedelic-like effects in mice. Therefore, 4-MeO-MiPT and other dual 5-HT_2A/SERT ligands may be therapeutically relevant compounds with reduced potential for traditional acute psychedelic effects.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 12","pages":"2348–2363"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.6c00083","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148024781","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":"Cu(ATSM) Restores Blood–Brain Barrier Abundance of P-Glycoprotein and Improves Cognitive Function in the APP/PS1 Mouse Model of Alzheimer’s Disease","authors":"Jae Pyun,&nbsp;Asif Noor,&nbsp;Pranav Runwal,&nbsp;Celeste Mawal,&nbsp;Oliver K. Fuller,&nbsp;Casey L. Egan,&nbsp;Mark A. Febbraio,&nbsp;Paul S. Donnelly,&nbsp;Jennifer L. Short,&nbsp;Ashley I. Bush* and Joseph A. Nicolazzo*,&nbsp;","doi":"10.1021/acschemneuro.6c00252","DOIUrl":"10.1021/acschemneuro.6c00252","url":null,"abstract":"<p >Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) peptides in the brain. P-glycoprotein (P-gp), a key efflux transporter at the blood–brain barrier (BBB), plays a crucial role in the clearance of Aβ. Using the APP/PS1 mouse model of familial AD, this study investigated the effect of copper diacetyl bis(4-methyl-3-thiosemicarbazone) (Cu(ATSM)) on brain microvascular abundance and function of P-gp and the associated effects on exogenous Aβ clearance, brain amyloid burden, and cognitive function. Compared to vehicle-treated 10 month-old APP/PS1 mice, Cu(ATSM) (30 mg/kg/day for 56 days) restored brain microvascular P-gp abundance (24.1%) and Cu concentrations (229.8%) as well as significantly reduced brain cortical concentrations of human Aβ42 (hAβ42) (42.1%) in APP/PS1 mice. Cu(ATSM) treatment led to a trend toward improved brain clearance (11.9%) of ¹²⁵I-Aβ42 that was cortically injected into APP/PS1 mice compared to vehicle-treated APP/PS1 mice. Importantly, Cu(ATSM) treatment led to significantly improved (43.8% <i>p</i> = 0.0087) learning and long-term spatial memory in APP/PS1 mice, assessed by the Barnes maze paradigm. Inductively coupled plasma mass spectrometric analysis revealed increased Cu concentrations in brain microvessel-enriched fractions. In APP/PS1 mice, Cu(ATSM) restored brain microvascular P-gp abundance, which was associated with lowered cortical hAβ42, and improved long-term spatial memory, indicating neurovascular target engagement accompanied by amyloid lowering and behavioral benefit. Together with established BBB penetration and ongoing safety and tolerability evaluation in neurodegenerative populations, these findings propose Cu(ATSM) as a potential therapeutic application of biometal modulation targeting neurovascular dysfunction and Aβ burden in AD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 12","pages":"2389–2405"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148100711","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":"Glucose-Dependent Insulinotropic Polypeptide Receptors Are Expressed in the Lateral Septum and Reduce Electrically-Evoked Dopamine Release as well as the Ability of Cocaine to Increase Extracellular Dopamine","authors":"Anna Marie Buchanan,&nbsp;Sonja Virkus,&nbsp;N. Dalton Fitzgerald,&nbsp;Cesar E. Hernandez,&nbsp;Kirk M. Habegger,&nbsp;Jeremy Day,&nbsp;Troy A. Hackett,&nbsp;J. Andrew Hardaway* and Aurelio Galli*,&nbsp;","doi":"10.1021/acschemneuro.5c00954","DOIUrl":"10.1021/acschemneuro.5c00954","url":null,"abstract":"<p >Tirzepatide, a dual agonist of the glucagon-like peptide 1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR), represents a new class of medication for obesity and type II diabetes treatment. Using laboratory mice, we show that GIPRs are present in the lateral septum (LS) in cells also expressing GLP-1R, particularly in the dorsolateral LS. Likewise, we show the coexpression of the dopamine (DA) D2 receptor (DRD2) in LS cells with GLP-1R in both the dorsolateral and intermediate portions of the LS. Using fast-scan cyclic voltammetry, we demonstrate that systemic GLP-1R or GIPR agonist treatment reduces both electrically evoked DA release in the LS and the ability of cocaine to increase extracellular DA levels. These data unveil a new central role for GIPR signaling and identify a potentially important cell type expressing both GLP-1R and GIPR upon which tirzepatide or other dual agonists may modulate DA homeostasis in the brain.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 12","pages":"2319–2323"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.5c00954","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148135929","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":"Discovery of VU6053371/BI03738809: A First-in-Class Selective and CNS-Penetrant mGlu3 Positive Allosteric Modulator (PAM) with Efficacy in a Preclinical Cognition Model","authors":"Caleb A. Jones,&nbsp;Renn A. Duncan,&nbsp;Kristen M. Gilliland,&nbsp;Carson W. Reed,&nbsp;Daniel H. Haymer,&nbsp;Paul K. Spearing,&nbsp;Rory A. Capstick,&nbsp;Bartholomew P. Roland,&nbsp;Paige Vinson,&nbsp;Marc Quitalig,&nbsp;Caroline Baggeroer,&nbsp;Natasha B. Billard,&nbsp;Jonathan W. Dickerson,&nbsp;Zixiu Xiang,&nbsp;Valerie M. Kramlinger,&nbsp;Olivier Boutaud,&nbsp;Julia Schlichtiger,&nbsp;Carrie K. Jones,&nbsp;Colleen M. Niswender,&nbsp;Hyekyung P. Cho,&nbsp;Jerri L. Rook,&nbsp;Carsten T. Wotjak,&nbsp;Matthias Freiwald,&nbsp;Riccardo Giovannini,&nbsp;Heiko Sommer,&nbsp;Scott Hobson,&nbsp;P. Jeffrey Conn,&nbsp;Bruce J. Melancon and Craig W. Lindsley*,&nbsp;","doi":"10.1021/acschemneuro.6c00325","DOIUrl":"10.1021/acschemneuro.6c00325","url":null,"abstract":"<p >Herein, we report the discovery and development of the first-in-class (FIC), selective, and centrally active metabotropic glutamate receptor subtype 3 (mGlu₃) positive allosteric modulator (PAM), VU6053371/BI03738809. A high-throughput screening campaign identified a potent and selective mGlu₃ PAM VU6048261/DI013166572 based on a tetra-substituted thiophene core but with poor DMPK properties. Chemical lead optimization efforts managed to dramatically improve protein binding and <i>in vivo</i> rat PK to afford VU6053371/BI03738809. With an FIC <i>in vivo</i> tool compound, VU6053371/BI03738809 demonstrated robust efficacy in rat novel object recognition (NOR) (minimum effective dose (MED) = 3 mg/kg PO) and a clear pharmacokinetic/pharmacodynamic (PK/PD) relationship (PD efficacy observed when free brain concentrations were at, or above, the rat mGlu₃ EC₅₀). Thus, selective activation of mGlu₃ represents a novel mechanism to address the cognitive impairment associated with schizophrenia (CIAS) and other neurodegenerative diseases. Moreover, the discovery of VU6053371/BI03738809 completes the group II mGlu receptor toolkit of <i>in vivo</i> PAM and NAM probes for both mGlu₂ and mGlu₃.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 12","pages":"2406–2418"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.6c00325","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148174955","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":"Parthenolide Ameliorates Alzheimer’s Disease Pathology by Suppressing Microglial Inflammation and Inflammation-Driven Amyloidogenesis via the HIF1α/NF-κB Axis","authors":"Xin Liu,&nbsp;Jie Liu,&nbsp;Pei-yang Wang,&nbsp;Jun-he Cui,&nbsp;Yu-meng Bu,&nbsp;Shan-shan Wu,&nbsp;Yan-hui Zhang* and Chuang Guo*,&nbsp;","doi":"10.1021/acschemneuro.6c00141","DOIUrl":"10.1021/acschemneuro.6c00141","url":null,"abstract":"<p >The treatment landscape for Alzheimer’s disease (AD) faces challenges such as prolonged drug development, high costs, and limited FDA-approved therapies. Given the pathological similarities between Early-Onset AD (EOAD) and Late-Onset AD (LOAD), repurposing existing drugs offers a promising strategy to expedite therapeutic development. In this study, weighted gene coexpression network analysis (WGCNA) was applied to identify AD-associated gene modules, followed by network pharmacology to screen candidate compounds. Parthenolide was selected based on blood–brain barrier permeability and disease relevance. Its effects were evaluated using LPS-stimulated BV2 microglia, N2a-sw and HT22 neuronal models, and transgenic AD mouse models. Transcriptomic integration, transcription factor enrichment, pharmacological inhibition, and <i>in vivo</i> behavioral and pathological analyses were employed to elucidate underlying mechanisms. Our findings reveal that parthenolide markedly suppressed microglial activation and reduced pro-inflammatory mediators via modulation of the HIF1α/NF-κB signaling axis. Bioinformatics analysis identified HIF1α as a key hub gene, which was experimentally validated using the selective inhibitor YC-1. Parthenolide attenuated inflammation-induced amyloidogenesis by downregulating amyloid β precursor protein (APP) expression and the γ-secretase component Aph-1A γ-Secretase Subunit (APH1α). <i>In vivo</i>, parthenolide administration significantly improved cognitive performance, reduced microglial activation, decreased β-amyloid plaque burden, and suppressed HIF1α/NF-κB-dependent inflammatory signaling in 5 × FAD mouse models. In conclusion, this study demonstrates that parthenolide exerts multitarget therapeutic effects in AD by concurrently suppressing neuroinflammation and amyloidogenic processing. Targeting the HIF1α/NF-κB axis may represent a promising strategy for modulating inflammatory-metabolic-amyloid networks in AD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 12","pages":"2364–2378"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147757293","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":"Lipid Droplet-Accumulating Microglia as a Therapeutic Node in Neurodegenerative Disease","authors":"Siqi Guo,&nbsp;Qingyu Zhang,&nbsp;Rui Guo,&nbsp;Liyuan Fu,&nbsp;Huaxu Zhu and Qichun Zhang*,&nbsp;","doi":"10.1021/acschemneuro.6c00284","DOIUrl":"10.1021/acschemneuro.6c00284","url":null,"abstract":"<p >Neurodegenerative disorders increasingly reflect failures of cellular state control rather than the linear accumulation of a single toxic lesion. Microglia become trapped in maladaptive states in which inflammatory activation is decoupled from effective cargo processing. Lipid droplet-accumulating microglia (LDAM) represent a recurrent convergence state across aging and neurodegeneration, characterized by persistent neutral lipid sequestration, reduced phagocytosis-to-degradation capacity, oxidative amplification, and chronic but functionally inefficient inflammation. LDAM emerges when lipid substrate influx exceeds the capacity of cholesterol efflux, lysosomal lipophagy, and mitochondrial β-oxidation, converting lipid droplets from transient buffers into stable metabolic anchors. This entrenchment is reinforced by mitochondrial exhaustion, vacuolar H⁺-ATPase-linked lysosomal deacidification, and inflammasome/interferon locking, often further amplified by cGAS-STING signaling. Together, these constraints converge on a state of metabolic-epigenetic locking that sustains permissive chromatin landscapes at pro-inflammatory loci. On this basis, state-resetting strategies are considered that rebalance lipid flux, restore organelle clearance capacity, and transiently restrain inflammatory amplification, while spatial multiomics and fluid biomarkers are discussed as candidate tools for stage- and niche-resolved stratification of combination interventions.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 12","pages":"2302–2318"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148147444","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}