ACS Chemical Neuroscience最新文献

{"title":"Bithiophene Scaffold for PET Imaging and Photosensitization as a Novel Theranostic Platform Targeting Amyloid-β Aggregates","authors":"Takahiro Akasaka,&nbsp;Hiroyuki Watanabe* and Masahiro Ono*,&nbsp;","doi":"10.1021/acschemneuro.6c00047","DOIUrl":"10.1021/acschemneuro.6c00047","url":null,"abstract":"<p >Amyloid β (Aβ) aggregates are primary targets for the diagnosis and curative treatment of Alzheimer’s disease (AD). While various theranostic agents targeting Aβ aggregates have been developed, most rely on fluorescent imaging, which has limited clinical translation. In contrast, nuclear medicine imaging, particularly positron emission tomography (PET), offers high sensitivity and deep tissue permeability suitable for clinical settings. Moreover, photosensitization has emerged as a promising strategy to attenuate Aβ toxicity. In this study, we designed and synthesized novel bithiophene derivatives as PET/photosensitization theranostic agents. Western blotting analysis and MALDI-TOF MS spectrometry demonstrated that FABT-2 selectively oxidized Aβ aggregates under light irradiation, leading to a significant reduction in Aβ-induced cytotoxicity, as demonstrated by CCK8 and LDH assays. Furthermore, ¹⁸F-labeled FABT-2 showed blood–brain barrier permeability in normal mice. These results suggest that FABT-2 may be a promising lead compound for the development of theranostic agents targeting Aβ aggregates.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 14","pages":"2588–2602"},"PeriodicalIF":4.5,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148349879","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 Assessment of Neurometabolism by Deuterium and Proton NMR Spectroscopy Using [6,6′-2H2]Glucose","authors":"Akila Ramesh,&nbsp;Ravinder Reddy and Anant Bahadur Patel*,&nbsp;","doi":"10.1021/acschemneuro.6c00030","DOIUrl":"10.1021/acschemneuro.6c00030","url":null,"abstract":"<p >Neurometabolic analysis is routinely performed using ¹³C NMR/MRS in conjunction with the administration of ¹³C-labeled tracers. Despite its widespread use, the low sensitivity of ¹³C NMR necessitates long acquisition times. To address this limitation, the present study introduces an indirect approach that uses a single ¹H NMR acquisition to measure deuterium labeling by exploiting labeling at specific sites, thereby providing a novel and more efficient strategy for assessing neurometabolism. In this study, male SD rats were infused with [6,6’-²H₂]glucose for 10–90 min, and the ²H labeling of cortical metabolites was measured <i>ex vivo</i> using ²H NMR spectroscopy. After 90 min of [6,6′-²H₂]glucose infusion, resonances corresponding to [3-²H₂]lactate, [4-²H_<i>x</i>]glutamate, [4-²H_<i>x</i>]glutamine, and [3-²H]aspartate (∼2.60 ppm) were detected. In contrast, signals corresponding to [2-²H]aspartate (∼3.90 ppm), [2-²H]glutamate (∼3.76 ppm), and [3-²H]glutamate (∼2.09 ppm) were not detected, even after prolonged infusion, suggesting complete loss of the ²H label during the second turn of the tricarboxylic acid cycle. The cerebral metabolic rate of glucose oxidation, estimated by fitting an exponentially saturating curve to the pooled labeling of [4-²H_<i>x</i>]glutamate, [4-²H_<i>x</i>]glutamine, and [3-²H]aspartate, was 0.389 ± 0.031 μmol/g/min. The [4-²H_<i>x</i>]glutamate levels were also derived by subtracting the [4-¹H₂]glutamate resonance intensity from total [4-¹H₂]glutamate intensity estimated using the [3-¹H₂]glutamate intensity in unedited ¹H NMR spectra. The concentrations of [4-²H_<i>x</i>]glutamate determined from ¹H NMR spectra were comparable to those determined from ²H NMR. Moreover, when applied to 5xFAD mice (2.53 ± 0.43 μmol/g, <i>n</i> = 7), a model of Alzheimer’s disease, this indirect approach revealed significantly reduced (<i>p</i> = 0.028) [4-²H_<i>x</i>]glutamate levels compared with controls (2.99 ± 0.15 μmol/g, <i>n</i> = 7). This decrease was comparable to that observed with the direct ²H NMR measurements and was consistent with findings from ¹³C tracer-based studies.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 14","pages":"2577–2587"},"PeriodicalIF":4.5,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148373675","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":"Status of Alzheimer’s and Parkinson’s Disease Detections and Treatments","authors":"Phuong H. Nguyen*,&nbsp; and ,&nbsp;Philippe Derreumaux,&nbsp;","doi":"10.1021/acschemneuro.6c00096","DOIUrl":"10.1021/acschemneuro.6c00096","url":null,"abstract":"<p >Alzheimer’s disease and related dementias affect more than 55 million people worldwide, a number projected to double by 2050 as populations age. Beyond the devastating personal toll on patients and families, the global economic burden is estimated at approximately $1.3 trillion annually. Despite more than a century of research since the initial descriptions of Parkinson’s disease (PD) in 1817 and Alzheimer’s disease (AD) in 1906, the fundamental drivers of these disorders and effective strategies to prevent their progression remain poorly understood, despite billions of dollars invested in research. For decades, the accumulation and deposition of oligomeric amyloid-β and tau in AD, and α-synuclein in PD, have dominated conceptual frameworks guiding research and therapeutic development. This narrow focus may help explain why antiamyloid therapies have yielded only modest clinical benefits. Consequently, current drug development pipelines are increasingly moving beyond the amyloid cascade hypothesis and the singular emphasis on α-synuclein. Meanwhile, AD continues to be frequently misdiagnosed or diagnosed at advanced stages, often after irreversible neurodegeneration has already occurred. Encouragingly, the past decade has witnessed a major transformation in the early and accurate diagnosis of AD and PD, driven by the emergence of more affordable and precise diagnostic tools. Together, these advances suggest that an integrated framework combining molecular, digital, imaging, and genetic approaches may ultimately enable earlier diagnosis, personalized intervention, and more effective disease modification in AD and PD, raising the possibility of slowing disease progression before extensive brain damage develops.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 13","pages":"2441–2453"},"PeriodicalIF":4.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148274941","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":"Pathogenic Modulation of Organelle Crosstalk in Helicobacter pylori-Associated Neurodegeneration","authors":"Meenakshi Kandpal,&nbsp;Harshita Shrivastava,&nbsp;Nfor Gael Njini,&nbsp;Srija Mukherjee,&nbsp;Sanjana Kumari,&nbsp;Ashutosh Srivastava,&nbsp;Awanish Kumar,&nbsp;Srikanth Karnati and Hem Chandra Jha*,&nbsp;","doi":"10.1021/acschemneuro.5c00930","DOIUrl":"10.1021/acschemneuro.5c00930","url":null,"abstract":"<p >Neurological disorders are increasingly linked to dysfunction of key cellular organelles, including mitochondria, endoplasmic reticulum (ER), lysosomes, endosomes, and peroxisomes. These organelles coordinate essential neuronal processes via tightly regulated crosstalk. Disruption in one organelle can propagate dysfunction across others, amplifying neurodegenerative cascades. Emerging evidence suggests that neurological diseases can result not only from disturbances in brain homeostasis but also from imbalances in gut homeostasis, highlighting the significant role of the gut-brain axis in maintaining neurological health. <i>Helicobacter pylori</i>, a gut pathogen contribute to the progression of neurological modalities by its secretome comprising Vac A, CagA, urease, and outer membrane vesicles via perturbing organelle function. These virulence factors induce mitochondrial fragmentation, ER stress, lysosomal dysfunction, and impaired mitophagy, disrupting organelle networks and promoting synaptic loss and neuronal death. Understanding how pathogen-induced organelle stress contributes to neurodegeneration offers novel insights into infection-driven brain disorders.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 13","pages":"2419–2440"},"PeriodicalIF":4.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148262360","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":"Xerogel-Engineered Graphitic Carbon Nitride Interfaces Enable Aptamer-Based Detection of Salivary Lactoferrin for Noninvasive Diagnosis of Alzheimer’s Disease","authors":"Bivas Talukdar,&nbsp;Damini Verma and Gopinath Packirisamy*,&nbsp;","doi":"10.1021/acschemneuro.5c00824","DOIUrl":"10.1021/acschemneuro.5c00824","url":null,"abstract":"<p >Alzheimer’s disease (AD), the primary cause of dementia, is a progressive neurodegenerative disorder that requires early diagnosis using noninvasive biosensing strategies. Salivary lactoferrin has consequently emerged as a compelling early-stage AD biomarker, as its dysregulated expression reflects underlying neuroinflammatory mechanisms associated with disease initiation and progression. Accordingly, we report an innovative aptamer-based electrochemical aptasensor for noninvasive and accurate biosensing of salivary lactoferrin (Lf). The design approach involves fabricating gold screen-printed electrodes (gSPEs) with <i>in situ</i> prepared porous graphitic carbon nitride (g-C₃N₄) xerogel using coprecipitation with the amino acid <span>l</span>-cysteine (<span>l</span>-Cys), followed by surface immobilization of the Lf aptamer and subsequent blocking with 6-mercapto-1-hexanol (MCH) <i>via</i> drop-casting. Structural and electrochemical characterizations indicate successful xerogel synthesis, where <span>l</span>-Cys acts as an interlayer-bridging agent, achieving high specificity and superior performance within a broad detection range of 0.5–500 μg mL^–1 based on the differential pulse voltammetry (DPV) technique. The aptasensor exhibits a significantly high sensitivity of 89.22 μA (log₁₀ μg mL^–1)⁻¹ cm^–2 and a low limit of detection (LOD) of 0.34 μg mL^–1 in the artificial saliva samples. Furthermore, our fabricated sensor shows good reproducibility and repeatability with %RSD values well below 5%, thereby strengthening the utility of our novel biosensor design for applications in the timely detection of AD biomarker in body fluids, both within clinical settings as well as in point-of-care (POC) diagnostics.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 13","pages":"2454–2468"},"PeriodicalIF":4.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148051111","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":"Neuropeptide Diversity Encoded in Newly Sequenced Crustacean Genomes Reveals Signaling Roles during Feeding","authors":"Lauren Fields,&nbsp;Vu Ngoc Huong Tran,&nbsp;Thao Duong,&nbsp;Tina C. Dang,&nbsp;Kendra G. Selby and Lingjun Li*,&nbsp;","doi":"10.1021/acschemneuro.6c00123","DOIUrl":"10.1021/acschemneuro.6c00123","url":null,"abstract":"<p >Neuropeptides are chemically diverse signaling molecules that regulate physiology and behavior, yet many species lack neuropeptidomic characterization due to sparse genomic annotation. Here, we integrate genomic sequence information with neuropeptidomics to define the neuropeptidomes of two widely used crustacean model organisms, <i>Callinectes sapidus</i> and <i>Cancer borealis</i>. Using a curated multispecies precursor database, tBLASTn alignment, signal peptide detection, and <i>in silico</i> processing, we predicted more than 23,000 putative peptides across both genomes, including numerous sequences bearing hallmarks of mature neuropeptides. Mass spectrometry-based profiling provided experimental support for many predicted peptides and revealed substantial chemical diversity, including novel allatostatin B and C isoforms, an insulin-like peptide B-chain-like isoform in <i>C. sapidus</i>, and the first report of natalisin peptides in <i>C. borealis</i>. Notably, we observed an atypical precursor architecture in which a single prohormone encoded two distinct neuropeptide families, suggesting previously unrecognized modes of neuropeptide copackaging and signaling. Finally, leveraging a feeding perturbation model, we observed tissue-specific differences in the abundance of newly identified peptides in the thoracic ganglion, commissural ganglion, and pericardial organs, consistent with functional neuroendocrine roles. Together, this work expands the known repertoire of crustacean neuropeptides, provides a resource for comparative peptide biology, and establishes a genome-enabled framework for discovery of endogenous peptide signaling molecules in newly sequenced species.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 13","pages":"2494–2503"},"PeriodicalIF":4.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.6c00123","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148222023","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":"Exploring the Neuroprotective Potential of 5-Azacytidine on the Streptozotocin-Induced Rat Model of Alzheimer’s Disease","authors":"Shivangi Paliwal,&nbsp;Jayant Singh Bhardwaj and Rajeev Taliyan*,&nbsp;","doi":"10.1021/acschemneuro.6c00234","DOIUrl":"10.1021/acschemneuro.6c00234","url":null,"abstract":"<p >Alzheimer’s disease (AD) associated with insulin resistance represents a major challenge in sporadic neurodegeneration, where impaired neuronal survival and synaptic plasticity are compounded by aberrant DNA methylation. Epigenetic silencing of Wnt pathway genes under insulin-resistant conditions exacerbates β-amyloid accumulation, tau hyperphosphorylation, and oxidative stress. The present study aimed to establish insulin-resistant AD models and evaluate the mechanistic potential of DNA methyltransferase (DNMT) inhibition, with a specific focus on canonical Wnt/β-catenin restoration. An in vitro AD model was generated by exposing SHSY-5Y cells to streptozotocin (STZ, 400 μM), resulting in elevated DNMT1, Aβ_1–42, and sFRP1 levels, alongside reduced β-catenin and survivin expression. Treatment with the DNMT1 inhibitor 5-azacytidine (5-AZA), employed here as a mechanistic probe rather than a therapeutic candidate, reversed these changes, restoring Wnt signaling and attenuating amyloid burden. In vivo, intracerebroventricular administration of STZ (3 mg/kg) in rats induced an insulin-resistant AD-like pathology characterized by cognitive decline, increased pTau and acetylcholinesterase activity, and reduced neuroprotective markers. 5-AZA treatment improved memory and behavior, decreased pTau and AChE levels, and enhanced ADAM10, TREM2, BDNF, and antioxidant activity. Histological analysis further revealed preservation of neuronal layers and structural integrity. Collectively, these findings demonstrate that DNMT inhibition, exemplified by 5-AZA as a mechanistic tool, can mitigate STZ-induced molecular and behavioral alterations by relieving hypermethylation-mediated repression and supporting partial reactivation of canonical Wnt/β-catenin signaling. While 5-AZA itself is not a viable therapeutic option, the results highlight DNMT inhibition as a promising disease-modifying strategy in insulin resistance-associated AD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 13","pages":"2517–2532"},"PeriodicalIF":4.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148292587","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":"Temperature-Dependent Dynamics of Aβ42 and α-Synuclein Monomers and Early Oligomerization of Aβ42: Shared Residues Mediate Intra- and Intermolecular β-Sheets","authors":"Gabriel F. Martins,&nbsp;Cristiano Rocha and Nuno Galamba*,&nbsp;","doi":"10.1021/acschemneuro.6c00242","DOIUrl":"10.1021/acschemneuro.6c00242","url":null,"abstract":"<p >We used molecular dynamics simulations to investigate how temperature modulates hydrophobic interactions and β-sheet formation in the CHARMM36m model of intrinsically disordered proteins, focusing on a monomer of amyloid-beta (Aβ42) and α-synuclein, as well as a dimer and tetramer of Aβ42. For the isolated monomers, increasing temperature leads to an increase in intramolecular contacts, promoting hydrogen bonding and secondary-structure reorganization toward β-sheet and turn motifs. Analysis of the dimer and tetramer of Aβ42 reveals increased conformational heterogeneity at high temperatures, suggesting a smaller-than-expected configurational entropy penalty upon association. Thus, whereas monomers undergo temperature-induced compaction, enhancing intramolecular interactions, including the formation of β-sheets, in the dimer and tetramer, hydrophobic stabilization is redirected toward aggregation, promoting cross-β-sheet formation, peptide elongation, and the emergence of spherical conformations. Notably, the residues that stabilize intramolecular β-sheets in the monomer (approximately sequences 16–22 and 29–36) largely overlap with those that form cross-β-sheet motifs in the aggregates, suggesting that intramolecular β-sheet formation is intrinsically linked to aggregation propensity. These results, in close agreement with earlier NMR measurements of the monomer and protofibrils, reveal a competition between intra- and intermolecular hydrophobic interactions, with intermolecular interactions ultimately becoming more favorable than the intramolecular interactions that stabilize monomer solvation.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 13","pages":"2504–2516"},"PeriodicalIF":4.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.6c00242","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300304","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":"Spontaneous Insertion of Aβ42 Dimers but Not Monomers into a Cholesterol-Rich Lipid Bilayer","authors":"Rachit Pandey,&nbsp;Thomas Ruggiero,&nbsp;Brian Andrews and Brigita Urbanc*,&nbsp;","doi":"10.1021/acschemneuro.5c00942","DOIUrl":"10.1021/acschemneuro.5c00942","url":null,"abstract":"<p >The leading Alzheimer’s disease (AD) hypothesis posits that oligomers formed by amyloid β-protein (Aβ), in particular 42-residue-long Aβ42, interact with a cellular membrane, causing a cascade of events leading to neurodegeneration. The modes of Aβ42-lipid interactions are not well understood. Here, we use explicit-solvent all-atom molecular dynamics (MD) to demonstrate that Aβ42 monomers interact with lipids differently than Aβ42 dimers. In our simulations, lipids in the absence and presence of Aβ42 form a lipid bilayer with a cholesterol-rich domain, resembling a lipid raft. Whereas lipids stabilize the Aβ42 monomer structure, they partially destabilize Aβ42 dimers. Unlike monomers, which interact exclusively with solvent-exposed lipid tails on one side of a bilayer, dimers exhibit additional modes of interactions with lipids, including spontaneous insertion into the cholesterol-rich domain of a bilayer and carpeting, thereby disrupting the lipid bilayer structure. Our findings provide a mechanistic explanation for why Aβ42 monomers are nontoxic and reveal that Aβ42 oligomer-induced toxicity emerges already at the stage of Aβ42 dimer formation.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 13","pages":"2469–2485"},"PeriodicalIF":4.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.5c00942","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147985390","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":"Pharmacokinetic Studies of Amyloid-Targeting Bis(styryl)benzene Agents for Alzheimer’s Disease","authors":"Kerui Xu,&nbsp;Jennifer A. Salaiza,&nbsp;Hammed Adeoye,&nbsp;Saumitra Bhowmik,&nbsp;Tarek El Sayed,&nbsp;Monika Rana and Liviu M. Mirica*,&nbsp;","doi":"10.1021/acschemneuro.6c00361","DOIUrl":"10.1021/acschemneuro.6c00361","url":null,"abstract":"<p >The pharmacokinetics (PK) and biodistribution of radiolabeled amyloid-β (Aβ)-targeting probes have been extensively characterized in the context of Alzheimer’s disease (AD), whereas the corresponding nonradiolabeled scaffolds remain largely unexplored <i>in vivo</i>. Herein, we report <i>in vivo</i> PK studies of the widely used amyloid probe methoxy-X04 (MeX04) in transgenic 5xFAD and wild-type (WT) mice. In plasma, MeX04 shows comparable exposure between 5xFAD and WT mice, indicating no major genotype-dependent differences in systemic clearance. In contrast, brain exposure was markedly increased in 5xFAD mice, with higher brain <i>C</i>_max and AUC parameters and slower washout, consistent with Aβ-dependent sequestration and retention in the AD brain tissue. Notably, fluorescence microscopy revealed that the fluorescence intensity of amyloid plaque-bound MeX04 closely mirrored the total brain concentration, and we employed <i>ex vivo</i> fluorescence intensity quantification to evaluate the PK of a related bis(styryl)benzene compound, LS-4, which is proposed to exhibit increased affinity for soluble Aβ aggregates. We then performed age-dependent ex vivo staining of compound-bound Aβ aggregates in 5xFAD brains, and LS-4 exhibits appreciable amyloid-bound fluorescence intensity in younger 5xFAD mice, consistent with its higher affinity for Aβ oligomers, whereas MeX04 exhibited stronger fluorescence intensity in older mice. Consequently, we propose an efficient approach to track temporal changes in the PK of Aβ-binding compounds by ex vivo evaluation of their amyloid-bound fluorescence intensity, providing a rapid assessment of the general PK trends of newly developed amyloid-binding probes.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 13","pages":"2533–2542"},"PeriodicalIF":4.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300289","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}