{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:37:39Z","timestamp":1789987059811,"version":"4.0.1"},"reference-count":43,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82374062"],"award-info":[{"award-number":["82374062"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82374062"],"award-info":[{"award-number":["82374062"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Central government-guided special fund project for local scientific and technological development","award":["YDZX2023003"],"award-info":[{"award-number":["YDZX2023003"]}]},{"name":"Central government-guided special fund project for local scientific and technological development","award":["YDZX2023137"],"award-info":[{"award-number":["YDZX2023137"]}]},{"name":"Shandong University of Traditional Chinese Medicine Youth Science Research Fund Project","award":["KYZK2024Q24"],"award-info":[{"award-number":["KYZK2024Q24"]}]},{"name":"Key Research and Development Program of Tibet Autonomous Region Science and Technology Plan Project","award":["XZ202601ZY0167"],"award-info":[{"award-number":["XZ202601ZY0167"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Alzheimer\u2019s disease (AD) is characterized by amyloid-beta accumulation and neuroinflammation, yet the molecular target of Ginsenoside Rg1 remains elusive. This study aimed to elucidate the neuroprotective mechanism of Ginsenoside Rg1, specifically investigating its interaction with C-C motif chemokine receptor 3 (CCR3). Methods: We utilized 5xFAD transgenic mice and CCR3-overexpressing BV2 microglial cells. Behavioral assessments, enzyme-linked immunosorbent assays, quantitative real-time polymerase chain reaction, molecular docking, and surface plasmon resonance were employed to evaluate cognitive function and molecular pathways. Results: Ginsenoside Rg1 treatment significantly ameliorated spatial learning and memory deficits. Quantitatively, Rg1 reduced cortical amyloid-beta 1\u201340 levels (p &lt; 0.05) and bound directly to CCR3 with a dissociation constant of 3.599 \u00d7 10\u22125 mol\/L. This inhibition suppressed neuroinflammation and restored neurotrophic factors, including Brain-derived neurotrophic factor. Conclusions: CCR3 is a novel pharmacological target for Ginsenoside Rg1, providing a precise molecular basis for its neuroprotective effects. Future research should focus on clarifying the pharmacokinetic profile and brain bioavailability of Ginsenoside Rg1 to facilitate clinical translation.<\/jats:p>","DOI":"10.3390\/ph19050661","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T17:26:18Z","timestamp":1777051578000},"page":"661","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ginsenoside Rg1 Ameliorates the Learning and Memory Deficits of 5xFAD Mice by Inhibiting CCR3 Activity: Insights from In Vivo and In Vitro Investigations"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3813-3194","authenticated-orcid":false,"given":"Hui","family":"Lu","sequence":"first","affiliation":[{"name":"Institute Innovation of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3404-0006","authenticated-orcid":false,"given":"Ying","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute Innovation of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute Innovation of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Li","sequence":"additional","affiliation":[{"name":"Institute Innovation of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyi","family":"Li","sequence":"additional","affiliation":[{"name":"Institute Innovation of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6939-009X","authenticated-orcid":false,"given":"Tianhao","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute Innovation of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixue","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute Innovation of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengzhen","family":"Li","sequence":"additional","affiliation":[{"name":"Institute Innovation of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8009-7217","authenticated-orcid":false,"given":"Xiaorui","family":"Cheng","sequence":"additional","affiliation":[{"name":"Institute Innovation of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2023). 2023 Alzheimer\u2019s Disease Facts and Figures. Alzheimer\u2019s Dement., 19, 1598\u20131695.","DOI":"10.1002\/alz.13016"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/S0006-291X(84)80190-4","article-title":"Alzheimer\u2019s Disease: Initial Report of the Purification and Characterization of a Novel Cerebrovascular Amyloid Protein","volume":"120","author":"Glenner","year":"1984","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s40035-024-00433-w","article-title":"Linking Apoe4\/4 Genotype to Microglial Lipid Droplets and Neurotoxicity in Alzheimer\u2019s Disease","volume":"13","author":"Huang","year":"2024","journal-title":"Transl. Neurodegener."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2024). 2024 Alzheimer\u2019s Disease Facts and Figures. Alzheimers Dement., 20, 3708\u20133821.","DOI":"10.1002\/alz.13809"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4807","DOI":"10.1016\/j.apsb.2025.07.005","article-title":"Pleiotropic Prodrugs for Both Symptomatic and Disease-Modifying Treatment of Alzheimer\u2019s Disease","volume":"15","author":"Meden","year":"2025","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s Disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4260","DOI":"10.1016\/j.cell.2023.08.021","article-title":"Alzheimer\u2019s Disease: From Immunotherapy to Immunoprevention","volume":"186","author":"Jucker","year":"2023","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7964","DOI":"10.1007\/s12035-016-0269-5","article-title":"Targeting Ccr3 to Reduce Amyloid-\u0392 Production, Tau Hyperphosphorylation, and Synaptic Loss in a Mouse Model of Alzheimer\u2019s Disease","volume":"54","author":"Zhu","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e2319057121","DOI":"10.1073\/pnas.2319057121","article-title":"Ccr3-Dependent Eosinophil Recruitment Is Regulated by Sialyltransferase St3gal-Iv","volume":"121","author":"Immler","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1161\/CIRCRESAHA.125.326599","article-title":"Macrophage-Derived Ccl24 Promotes Cardiac Fibrosis via Fibroblast Ccr3","volume":"137","author":"Parthiban","year":"2025","journal-title":"Circ. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"112753","DOI":"10.1016\/j.celrep.2023.112753","article-title":"Rebalancing Liver-Infiltrating Ccr3+ and Cd206+ Monocytes Improves Diet-Induced Nafld","volume":"42","author":"Sun","year":"2023","journal-title":"Cell Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1165\/rcmb.2020-0425OC","article-title":"Platelets Independently Recruit into Asthmatic Lungs and Models of Allergic Inflammation via Ccr3","volume":"64","author":"Shah","year":"2021","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2019.05.022","article-title":"The Small Molecular Ccr3 Antagonist Ym344031 Attenuates Neurodegenerative Pathologies and Improves Learning and Memory Performance in a Mouse Model of Alzheimer\u2019s Disease","volume":"1719","author":"Sui","year":"2019","journal-title":"Brain Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"110379","DOI":"10.1016\/j.isci.2024.110379","article-title":"Ccr3 Knockdown Attenuates Prolonged Underwater Operations-Induced Cognitive Impairment via Alleviating Microglia-Mediated Neuroinflammation","volume":"27","author":"Zhao","year":"2024","journal-title":"iScience"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3238","DOI":"10.1016\/j.cell.2025.03.041","article-title":"Immunotherapy-Related Cognitive Impairment after Car T Cell Therapy in Mice","volume":"188","author":"Geraghty","year":"2025","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ivanovska, M., Abdi, Z., Murdjeva, M., Macedo, D., Maes, A., and Maes, M. (2020). Ccl-11 or Eotaxin-1: An Immune Marker for Ageing and Accelerated Ageing in Neuro-Psychiatric Disorders. Pharmaceuticals, 13.","DOI":"10.20944\/preprints202001.0370.v1"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/j.jad.2020.05.062","article-title":"Eotaxin-1\/Ccl11 Correlates with Left Superior Temporal Gyrus in Bipolar Disorder: A Preliminary Report Suggesting Ac-celerated Brain Aging","volume":"273","author":"Mohite","year":"2020","journal-title":"J. Affect. Disord."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Tashiro, R., Ozaki, D., Bautista-Garrido, J., Sun, G., Obertas, L., Mobley, A.S., Kim, G.S., Aronowski, J., and Jung, J.E. (2023). Young Astrocytic Mitochondria Attenuate the Elevated Level of Ccl11 in the Aged Mice, Contributing to Cognitive Function Improvement. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065187"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s11011-019-00512-2","article-title":"Increased Inflammation in Ba21 Brain Tissue from African Americans with Alzheimer\u2019s Disease","volume":"35","author":"Ferguson","year":"2020","journal-title":"Metab. Brain Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.3233\/JAD-220716","article-title":"The Ccl2 Rs4586 Snp Is Associated with Slower Amyloid-\u0392 Deposition and Faster Tau Accumulation of Alzheimer\u2019s Disease","volume":"90","author":"Gao","year":"2022","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"110139","DOI":"10.1016\/j.biopha.2020.110139","article-title":"Pananx Notoginseng Saponins Attenuate Ccl2-Induced Cognitive Deficits in Rats via Anti-Inflammation and Anti-Apoptosis Effects That Involve Suppressing over-Activation of Nmda Receptors","volume":"127","author":"Zhou","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13195-022-01159-5","article-title":"Convergent Transcriptomic and Genomic Evidence Supporting a Dysregulation of Cxcl16 and Ccl5 in Alzheimer\u2019s Disease","volume":"15","author":"Li","year":"2023","journal-title":"Alzheimers Res. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.jgr.2022.12.001","article-title":"Ginsenoside Rg1 Ameliorates Alzheimer\u2019s Disease Pathology via Restoring Mitophagy","volume":"47","author":"Wang","year":"2023","journal-title":"J. Ginseng Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.jgr.2022.12.006","article-title":"Ginsenoside Rg1 Treatment Protects against Cognitive Dysfunction via Inhibiting Plc-Cn-Nfat1 Signaling in T2dm Mice","volume":"47","author":"Dong","year":"2023","journal-title":"J. Ginseng Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13020-020-00325-x","article-title":"Ginsenoside Rg1 Alleviates Repeated Alcohol Exposure-Induced Psychomotor and Cognitive Deficits","volume":"15","author":"Huang","year":"2020","journal-title":"Chin. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.7150\/ijms.43979","article-title":"Ginsenoside Rg1 Ameliorates the Cognitive Deficits in D-Galactose and Alcl(3)-Induced Aging Mice by Restoring Fgf2-Akt and Bdnf-Trkb Signaling Axis to Inhibit Apoptosis","volume":"17","author":"Zhong","year":"2020","journal-title":"Int. J. Med. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"118205","DOI":"10.1016\/j.jep.2024.118205","article-title":"Ginsenoside Rg1 Alleviates Chronic Inflammation-Induced Neuronal Ferroptosis and Cognitive Impairments via Regulation of Aim2-Nrf2 Signaling Pathway","volume":"330","author":"Kong","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3892\/mmr.2022.12893","article-title":"Ginsenoside Rg1 Alleviates Learning and Memory Impairments and A\u03b2 Disposition through Inhibiting Nlrp1 Inflam-masome and Autophagy Dysfunction in App\/Ps1 Mice","volume":"27","author":"Li","year":"2023","journal-title":"Mol. Med. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.jgr.2021.03.003","article-title":"Ginsenoside Rg1 Alleviates A\u03b2 Deposition by Inhibiting Nadph Oxidase 2 Activation in App\/Ps1 Mice","volume":"45","author":"Zhang","year":"2021","journal-title":"J. Ginseng Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"113999","DOI":"10.1016\/j.jpba.2021.113999","article-title":"Exploration of Tissue Distribution of Ginsenoside Rg1 by Lc-Ms\/Ms and Nanospray Desorption Electrospray Ionization Mass Spectrometry","volume":"198","author":"Wei","year":"2021","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Yang, X., Ye, T., He, Y., Wen, L., and Cheng, X. (2023). Qi-Fu-Yin Attenuated Cognitive Disorders in 5xfad Mice of Alzheimer\u2019s Disease Animal Model by Regulating Immunity. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1183764"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/s42003-023-04665-w","article-title":"Ccr3 Plays a Role in Murine Age-Related Cognitive Changes and T-Cell Infiltration into the Brain","volume":"6","author":"Rege","year":"2023","journal-title":"Commun. Biol."},{"key":"ref_33","first-page":"37","article-title":"Ginsenoside Rg1 Improves Pathological Damages by Activating the p21-p53-STK Pathway in Ovary and Bax-Bcl2 in the Uterus in Premature Ovarian Insufficiency Mouse Models","volume":"23","author":"He","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_34","first-page":"507","article-title":"Differentiation and Identification of Eosinophil Derived from Bone Marrow Cells of Mice","volume":"38","author":"Ma","year":"2018","journal-title":"J. Xuzhou Med. Univ."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.3233\/JAD-143120","article-title":"Gene Dosage Dependent Aggravation of the Neurological Phenotype in the 5xfad Mouse Model of Alzheimer\u2019s Disease","volume":"45","author":"Richard","year":"2015","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.jgr.2021.08.001","article-title":"Ginsenoside Rg1 Attenuates Cerebral Ischemia-Reperfusion Injury Due to Inhibition of Nox2-Mediated Calcium Homeo-stasis Dysregulation in Mice","volume":"46","author":"Han","year":"2022","journal-title":"J. Ginseng Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"267","DOI":"10.14336\/AD.2021.0720","article-title":"Cognitive Impairment and Metabolite Profile Alterations in the Hippocampus and Cortex of Male and Female Mice Exposed to a Fat and Sugar-Rich Diet Are Normalized by Diet Reversal","volume":"13","author":"Mohr","year":"2022","journal-title":"Aging Dis."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Gri\u00f1\u00e1n-Ferr\u00e9, C., Izquierdo, V., Otero, E., Puigoriol-Illamola, D., Corpas, R., Sanfeliu, C., Ortu\u00f1o-Sahag\u00fan, D.l., and Pall\u00e0s, M. (2018). Environmental Enrichment Improves Cognitive Deficits, Ad Hallmarks and Epigenetic Alterations Presented in 5xfad Mouse Model. Front Cell. Neurosci., 12.","DOI":"10.3389\/fncel.2018.00224"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40035-023-00388-4","article-title":"Blockage of Vegf Function by Bevacizumab Alleviates Early-Stage Cerebrovascular Dysfunction and Improves Cognitive Function in a Mouse Model of Alzheimer\u2019s Disease","volume":"13","author":"Zhang","year":"2024","journal-title":"Transl. Neurodegener."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Huang, X., Yang, J., Huang, X., Zhang, Z., Liu, J., Zou, L., and Yang, X. (2021). Tetramethylpyrazine Improves Cognitive Impairment and Modifies the Hippocampal Proteome in Two Mouse Models of Alzheimer\u2019s Disease. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.632843"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3233\/JAD-215063","article-title":"Adiponectin Ameliorates Cognitive Behaviors and in Vivo Synaptic Plasticity Impairments in 3xtg-Ad Mice","volume":"85","author":"Yan","year":"2022","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_42","first-page":"71","article-title":"An Improvement of the 2\u02c6(-delta delta CT) Method for Quantitative Real-Time Polymerase Chain Reaction Data Analysis","volume":"3","author":"Rao","year":"2013","journal-title":"Biostat. Bioinform. Biomath."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"Autodock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/5\/661\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T04:24:11Z","timestamp":1777091051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/5\/661"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,23]]},"references-count":43,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ph19050661"],"URL":"https:\/\/doi.org\/10.3390\/ph19050661","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,23]]}}}