{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:29:45Z","timestamp":1790890185187,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T00:00:00Z","timestamp":1751155200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Science Foundation of China","doi-asserted-by":"publisher","award":["32471351"],"award-info":[{"award-number":["32471351"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: To study the efficacy and pharmacological mechanism of the dual-target liposome complex AD808 in the treatment of Alzheimer\u2019s disease. Methods: Using APP\/PS1 mouse models, the therapeutic efficacy and pharmacological mechanism of AD808 on Alzheimer\u2019s disease were studied through water maze tests, brain tissue staining, immunofluorescence, and ELISA for inflammatory and neurotrophic factors. Results: AD808 exhibited significant pharmacodynamic effects in improving behavioral and cognitive abilities (70% reduction in escape latency) and repairing damaged nerve cells (90% reduction in A\u03b2 plaque) in Alzheimer\u2019s disease mice. The efficacy of the liposome complex AD808 was significantly better than that of ST707 or gh625-Zn7MT3 alone. AD808 significantly reduced brain inflammation (57.3% and 61.5% reductions in TNF-\u03b1 and IL-1\u03b2, respectively) in AD (Alzheimer\u2019s disease) mouse models and promoted the upregulation of neurotrophic factors and nerve growth factors (142.8% increase in BDNF, 275.9% in GDNF, and 111.3% in NGF-1) in brain homogenates. By activating the PI3K\/AKT signaling pathway in brain microglia, AD808 upregulated TREM2 protein expression and removed A\u03b2 amyloid plaques in the brain. Additionally, it promoted the transition of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, regulated the M1\/M2 balance, released anti-inflammatory and neurotrophic factors, reduced chronic inflammation, and enhanced neurological repair. Based on these results, the potential pharmacological mechanism of AD808 against Alzheimer\u2019s disease was proposed. Conclusions: As a dual-target liposome complex, AD808 has shown promising therapeutic potential in the treatment of Alzheimer\u2019s disease, providing a new strategy for innovative drug development.<\/jats:p>","DOI":"10.3390\/ph18070977","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T07:55:43Z","timestamp":1751442943000},"page":"977","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Study on the Pharmacological Efficacy and Mechanism of Dual-Target Liposome Complex AD808 Against Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"18","author":[{"given":"Chang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Chemistry, Fudan University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3097-0894","authenticated-orcid":false,"given":"Xiaoqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Fudan University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing 314000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songli","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Fudan University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueru","family":"Zhang","sequence":"additional","affiliation":[{"name":"Hangzhou Orenstar Biomed Co., Ltd., Hangzhou 314000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiming","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Fudan University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangshi","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Fudan University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/S0140-6736(19)30427-1","article-title":"Mortality, morbidity, and risk factors in China and its provinces, 1990\u20132017: A systematic analysis for the Global Burden of Disease Study 2017","volume":"394","author":"Zhou","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/s40120-022-00338-8","article-title":"Alzheimer\u2019s Disease: Epidemiology and Clinical Progression","volume":"11","author":"Byrnes","year":"2022","journal-title":"Neurol. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.jalz.2017.12.006","article-title":"The cost of Alzheimer\u2019s disease in China and re-estimation of costs worldwide","volume":"14","author":"Jia","year":"2018","journal-title":"Alzheimers Dement."},{"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":"675","DOI":"10.1016\/j.neurobiolaging.2003.12.026","article-title":"The microglial phagocytic role with specific plaque types in the Alzheimer disease brain","volume":"25","author":"Cole","year":"2004","journal-title":"Neurobiol. Aging"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.jfma.2015.04.001","article-title":"Current and novel therapeutic molecules and targets in Alzheimer\u2019s disease","volume":"115","author":"Kumar","year":"2016","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer\u2019s Disease: Causes and Treatment. Molecules, 25.","DOI":"10.3390\/molecules25245789"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/S1474-4422(22)00168-5","article-title":"Tau biomarkers in Alzheimer\u2019s disease: Towards implementation in clinical practice and trials","volume":"21","author":"Ossenkoppele","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1038\/bjc.1989.349","article-title":"Anti-inflammation induced by counter-irritation or by treatment with non-steroidal agents inhibits the growth of a tumour of non-detected immunogenicity","volume":"60","author":"Sordelli","year":"1989","journal-title":"Br. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"xiii","DOI":"10.1016\/j.ncl.2020.08.006","article-title":"Next Steps for Clinical Neurotoxicology","volume":"38","author":"Dobbs","year":"2020","journal-title":"Neurol. Clin."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1021\/tx900358j","article-title":"The Cu(II)\/Abeta\/human serum albumin model of control mechanism for copper-related amyloid neurotoxicity","volume":"23","author":"Bal","year":"2010","journal-title":"Chem. Res. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0006-8993(00)03196-6","article-title":"Metallothionein III is reduced in Alzheimer\u2019s disease","volume":"894","author":"Yu","year":"2001","journal-title":"Brain Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Xu, W., Xu, Q., Cheng, H., and Tan, X. (2017). The Efficacy and Pharmacological Mechanism of Zn(7)MT3 to Protect against Alzheimer\u2019s Disease. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-12800-x"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"854","DOI":"10.2174\/1567205020666230203112351","article-title":"Roles of Microglia in AD Pathology","volume":"19","author":"Rong","year":"2023","journal-title":"Curr. Alzheimer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1084\/jem.20151948","article-title":"TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques","volume":"213","author":"Wang","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.neuron.2018.01.031","article-title":"TREM2 Is a Receptor for beta-Amyloid that Mediates Microglial Function","volume":"97","author":"Zhao","year":"2018","journal-title":"Neuron"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1016\/j.jalz.2014.12.009","article-title":"The role of TREM2 R47H as a risk factor for Alzheimer\u2019s disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson\u2019s disease","volume":"11","author":"Lill","year":"2015","journal-title":"Alzheimers Dement."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2949","DOI":"10.1038\/npp.2014.164","article-title":"Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer\u2019s disease","volume":"39","author":"Jiang","year":"2014","journal-title":"Neuropsychopharmacology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1186\/1742-2094-8-187","article-title":"Interferon regulatory factor 3 plays an anti-inflammatory role in microglia by activating the PI3K\/Akt pathway","volume":"8","author":"Tarassishin","year":"2011","journal-title":"J. Neuroinflamm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.bbi.2019.07.004","article-title":"Efficacy and mechanism of cGAMP to suppress Alzheimer\u2019s disease by elevating TREM2","volume":"81","author":"Xu","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.freeradbiomed.2021.12.004","article-title":"Neuroinflammation-mediated mitochondrial dysregulation involved in postoperative cognitive dysfunction","volume":"178","author":"Yang","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1038\/nn1997","article-title":"Microglia: Active sensor and versatile effector cells in the normal and pathologic brain","volume":"10","author":"Hanisch","year":"2007","journal-title":"Nat. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/j.celrep.2019.03.099","article-title":"The Major Risk Factors for Alzheimer\u2019s Disease: Age, Sex, and Genes Modulate the Microglia Response to Abeta Plaques","volume":"27","author":"Frigerio","year":"2019","journal-title":"Cell Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1007\/s12031-019-01454-1","article-title":"TSPO Modulates IL-4-Induced Microglia\/Macrophage M2 Polarization via PPAR-gamma Pathway","volume":"70","author":"Zhou","year":"2020","journal-title":"J. Mol. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Duarte Azevedo, M., Sander, S., and Tenenbaum, L. (2020). GDNF, A Neuron-Derived Factor Upregulated in Glial Cells during Disease. J. Clin. Med., 9.","DOI":"10.3390\/jcm9020456"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.ymeth.2015.04.021","article-title":"Virtual screening, ADMET profiling, molecular docking and dynamics approaches to search for potent selective natural molecules based inhibitors against metallothionein-III to study Alzheimer\u2019s disease","volume":"83","author":"Roy","year":"2015","journal-title":"Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3683","DOI":"10.1007\/s00018-012-1047-9","article-title":"Characterization of the role of metallothionein-3 in an animal model of Alzheimer\u2019s disease","volume":"69","author":"Manso","year":"2012","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s11010-006-2390-7","article-title":"Metallothionein-3 and neuronal nitric oxide synthase levels in brains from the Tg2576 mouse model of Alzheimer\u2019s disease","volume":"283","author":"Martin","year":"2006","journal-title":"Mol. Cell. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1084\/jem.20142322","article-title":"TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer\u2019s disease mouse models","volume":"212","author":"Jay","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11524","DOI":"10.1073\/pnas.1710311114","article-title":"TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy","volume":"114","author":"Leyns","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"117031","DOI":"10.1016\/j.jep.2023.117031","article-title":"Qingxin Kaiqiao Fang decreases Tau hyperphosphorylation in Alzheimer\u2019s disease via the PI3K\/Akt\/GSK3beta pathway in vitro and in vivo","volume":"318","author":"Liu","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1007\/s12035-021-02611-7","article-title":"Implications of Phosphoinositide 3-Kinase-Akt (PI3K-Akt) Pathway in the Pathogenesis of Alzheimer\u2019s Disease","volume":"59","author":"Kumar","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/alzrt265","article-title":"Dietary regulation of PI3K\/AKT\/GSK-3beta pathway in Alzheimer\u2019s disease","volume":"6","author":"Kitagishi","year":"2014","journal-title":"Alzheimers Res. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Wang, C., Zong, S., Cui, X., Wang, X., Wu, S., Wang, L., Liu, Y., and Lu, Z. (2023). The effects of microglia-associated neuroinflammation on Alzheimer\u2019s disease. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1117172"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/ahg.12410","article-title":"Mini-review: Role of the PI3K\/Akt pathway and tyrosine phosphatases in Alzheimer\u2019s disease susceptibility","volume":"85","author":"Curtis","year":"2021","journal-title":"Ann. Hum. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1159\/000489155","article-title":"Upregulation of TREM2 Ameliorates Neuroinflammatory Responses and Improves Cognitive Deficits Triggered by Surgical Trauma in Appswe\/PS1dE9 Mice","volume":"46","author":"Jiang","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.bbamem.2014.10.006","article-title":"gH625: A milestone in understanding the many roles of membranotropic peptides","volume":"1848","author":"Galdiero","year":"2015","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Iachetta, G., Falanga, A., Molino, Y., Masse, M., Jab\u00e8s, F., Mechioukhi, Y., Laforgia, V., Khrestchatisky, M., Galdiero, S., and Valiante, S. (2019). gH625-liposomes as tool for pituitary adenylate cyclase-activating polypeptide brain delivery. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-45137-8"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1089\/hum.2023.025","article-title":"Fusion of Rabies Virus Glycoprotein or gh625 to Iduronate-2-Sulfatase for the Treatment of Mucopolysaccharidosis Type II","volume":"35","author":"Wood","year":"2024","journal-title":"Hum. Gene. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Barra, T., Falanga, A., Bellavita, R., Pisano, J., Laforgia, V., Prisco, M., Galdiero, S., and Valiante, S. (2022). Neuroprotective Effects of gH625-lipoPACAP in an In Vitro Fluid Dynamic Model of Parkinson\u2019s Disease. Biomedicines, 10.","DOI":"10.3390\/biomedicines10102644"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/s13041-020-00654-w","article-title":"Metallothionein-3 as a multifunctional player in the control of cellular processes and diseases","volume":"13","author":"Koh","year":"2020","journal-title":"Mol. Brain"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/nchembio.89","article-title":"Metal swap between Zn7-metallothionein-3 and amyloid-beta-Cu protects against amyloid-beta toxicity","volume":"4","author":"Meloni","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/1756-6606-3-30","article-title":"Roles of zinc and metallothionein-3 in oxidative stress-induced lysosomal dysfunction, cell death, and autophagy in neurons and astrocytes","volume":"3","author":"Lee","year":"2010","journal-title":"Mol. Brain"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Zhong, L., Zhang, Z.-L., Li, X., Liao, C., Mou, P., Wang, T., Wang, Z., Wang, Z., Wei, M., and Xu, H. (2017). TREM2\/DAP12 Complex Regulates Inflammatory Responses in Microglia via the JNK Signaling Pathway. Front. Aging Neurosci., 9.","DOI":"10.3389\/fnagi.2017.00204"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.3233\/JAD-150926","article-title":"Brain-Specific Basal and Novelty-Induced Alternations in PI3K-Akt and MAPK\/ERK Signaling in a Middle-Aged AbetaPP\/PS1 Mouse Model of Alzheimer\u2019s Disease","volume":"51","author":"Guillot","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.2174\/1567205014666170203141717","article-title":"Neuroinflammation and Alzheimer\u2019s Disease: Implications for Microglial Activation","volume":"14","author":"Regen","year":"2017","journal-title":"Curr. Alzheimer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1080\/08982104.2020.1806872","article-title":"Multifunctional osthole liposomes and brain targeting functionality with potential applications in a mouse model of Alzheimer\u2019s disease","volume":"31","author":"Ni","year":"2021","journal-title":"J. Liposome Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/978-1-4939-9554-7_20","article-title":"Overview on Emotional Behavioral Testing in Rodent Models of Pediatric Epilepsy","volume":"2011","author":"Medlej","year":"2019","journal-title":"Methods Mol. Biol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/7\/977\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:01:13Z","timestamp":1760032873000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/7\/977"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,29]]},"references-count":48,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ph18070977"],"URL":"https:\/\/doi.org\/10.3390\/ph18070977","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,29]]}}}