Mazdutide improves cognitive function in APP/PS1/Tau triple transgenic mice

doi:10.12307/2026.897

Abstract

Abstract: BACKGROUND: The pathological process of Alzheimer's disease is closely related to β-amyloid/Tau deposition and cerebrovascular dysfunction, and existing therapies are difficult to effectively intervene. In recent years, research on glucagon-like peptide-1 receptor agonists for the treatment of Alzheimer's disease has gained increasing popularity. As a novel dual agonist of the glucagon-like peptide-1 receptor and glucagon receptor, the therapeutic mechanism of Mazdutide in Alzheimer’s disease remains to be elucidated.
OBJECTIVE: To systematically explore the mechanism by which Mazdutide improves cognitive function in Alzheimer’s disease using a strategy combining network pharmacology and experimental validation, and to identify its potential core molecular targets, providing a theoretical basis for developing new treatment strategies for this disease.
METHODS: A multi-omics integration strategy was employed: Alzheimer’s disease-Mazdutide co-localization targets were screened based on the DisGeNET and SEA databases; protein-protein interaction networks were constructed via STRING, and core hub genes were identified through Cytoscape topology analysis; in APP/PS1/Tau triple transgenic Alzheimer’s disease mice, cognitive function was assessed following intraperitoneal injection of mazdutide (30 nmol/kg) using the Morris water maze, novel object recognition, and Y-maze tests. Western blot was used to detect hippocampal Aβ (6E10), p-Tau181, and endothelin receptor A expression.
RESULTS AND CONCLUSION: (1) Fifty-two co-localized targets were identified, with endothelin receptor A ranking as the top hub gene. (2) Mazdutide significantly improved cognition in 3xTg mice: spatial memory latency was shortened, episodic memory recognition index was enhanced, spontaneous alternation accuracy in working memory was increased, hippocampal pathological load was reduced, p-Tau181 levels were decreased, and EDNRA overexpression was suppressed. (3) Gene Ontology/Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed core pathways: in biological processes, the most significantly enriched terms included regulation of blood pressure and regulation of amine transport; cellular component analysis showed primary enrichment in symmetric synapses, sperm head, and pseudopodium structures; in molecular function, G protein-coupled peptide receptor activity, peptide receptor activity, and neuropeptide receptor activity dominated; in Kyoto Encyclopedia of Genes and Genomes pathway analysis, neuroactive ligand-receptor interaction, calcium signaling pathway, and hormone signaling were the three most significant pathways. (4) This study confirmed that Mazdutide may alleviate neuronal pathological damage and multi-dimensionally reverse cognitive impairment in Alzheimer’s disease by targeting and inhibiting EDNRA overexpression. The discovery of EDNRA provides a novel therapeutic target for Alzheimer’s disease.

Key words: Alzheimer’s disease, Mazdutide, network pharmacology, endothelin receptor A, bioinformatics

CLC Number:

Yuan Jingjing, Zhang Xiaomin, Du Pengyang, Wang Weifeng. Mazdutide improves cognitive function in APP/PS1/Tau triple transgenic mice[J]. Chinese Journal of Tissue Engineering Research, 2026, 30(34): 8962-8969.

Figures/Tables 8

显增加(P=0.022 3)，提示玛仕度肽可以改善3xTg小鼠的长期学习记忆能力。 2.4.2 玛仕度肽可以改善APP/PS1/Tau小鼠的情景记忆识别能力实验设计示意图见图5A。如图5B-D所示，WT组、3xTg组、3xTg+Maz组探索物体1的时间百分比分别为(37.50±3.27)%、(36.67±3.61)%、(39.17±3.18)%；探索物体2的时间百分比分别为(36.17±4.62)%、(35.50±7.14)%、(37.17±4.44)%，各组小鼠探索物体1和物体2的时间无统计学差异。WT组、3xTg组、3xTg+Maz组的识别指数分别为(40.51±2.75)%、(31.28±6.76)%、(39.44±4.86)%，3xTg组的识别指数明显低于WT组(P=0.016 9)，提示3xTg小鼠的情景记忆识别能力明显下降；3xTg+Maz组的识别指数明显高于3xTg组(P=0.034 8)，提示玛仕度肽可以改善3xTg小鼠的情景记忆识别能力。 2.4.3 玛仕度肽可以改善APP/PS1/Tau小鼠的短期学习记忆能力实验设计示意图见图6A。如图6B所示，WT组、3xTg组、3xTg+Maz组小鼠的总进臂次数分别为36.00±3.67，33.00±3.14，36.00±3.08，各组小鼠总进臂次数无统计学差异。如图6C所示，各组小鼠自发交替正确率分别为(46.13±5.08)%、(38.12±5.42)%、(46.29±5.08)%，3xTg组小鼠的自发交替正确率明显低于WT组(P=0.046 2)，提示3xTg小鼠的短期学习记忆能力明显下降；3xTg+Maz组小鼠的自发交替正确率明显高于3xTg组(P=0.041 8)，提示玛仕度肽可以改善3xTg小鼠的短期学习记忆能力。 2.4.4 玛仕度肽可以改善APP/PS1/Tau小鼠的β-淀粉样蛋白沉积和Tau蛋白异常磷酸化 6E10抗体是研究β-淀粉样蛋白沉积的金标准克隆亚型，广泛用于评估β-淀粉样蛋白的表达水平。Tau蛋白是神经元内主要的微管相关蛋白之一，属于低分子质量含磷糖蛋白。在阿尔茨海默病的早期阶段，血浆磷酸化Tau(p-Tau)水平呈进行性升高趋势。大规模临床研究证实，血浆p-Tau能有效区分阿尔茨海默病痴呆与非阿尔茨海默病神经退行性疾病相关的痴呆。此外，在轻度认知障碍患者中，p-Tau(尤其是Thr181位点磷酸化的亚型p-Tau181)已被证明可准确预测未来2-6年内出现的认知能力下降及其向阿尔茨海默病痴呆的转化。因而此次研究选用6E10和p-Tau181以评估玛仕度肽对3xTg小鼠脑内典型阿尔茨海默病病理表现的改善作用。如图7所示，6E10在WT组、3xTg组、3xTg+Maz组小鼠脑海马组织中的相对表达量分别为0.35±0.08，1.02±0.20，0.65± 0.18，3xTg组小鼠脑海马组织中6E10的表达量明显高于WT组(P < 0.001)，提示阿尔茨海默病小鼠模型中存在大量β-淀粉样蛋白1-16沉积；3xTg+Maz组小鼠脑海马组织中6E10的表达量明显低于3xTg组(P=0.004 2)，提示玛仕度肽可以改善3xTg小鼠脑海马组织中的β-淀粉样蛋白1-16沉积。 p-Tau181在WT组、3xTg组、3xTg+Maz组小鼠脑海马组织中的相对表达量分别为0.29±0.09，0.72±0.12，0.51±0.14，3xTg组小鼠脑海马组织中p-Tau181的表达量明显高于WT组(P < 0.001)，提示阿尔茨海默病小鼠模型中存在大量异常磷酸化Tau蛋白；3xTg+Maz组小鼠脑海马组织中p-Tau181的表达量明显低于3xTg组(P=0.026 7)，提示玛仕度肽可以改善3xTg小鼠脑海马组织中的Tau蛋白异常磷酸化。以上得出结论，玛仕度肽可以改善3xTg小鼠的典型阿尔茨海默病病理表现：β-淀粉样蛋白沉积和Tau蛋白异常磷酸化。 2.4.5 玛仕度肽可能通过抑制EDNRA过表达治疗阿尔茨海默病 EDNRA为前期网络药理学筛选出的TOP1核心靶点。如图8所示，EDNRA在WT组、3xTg组、3xTg+Maz组小鼠脑组织中的相对表达量分别为0.39±0.06，0.79±0.07，0.63±0.08，与对照WT组相比，3xTg组EDNRA的相对表达量明显上调(P < 0.001)，提示阿尔茨海默病小鼠模型存在异常过表达的EDNRA；而3xTg+Maz组EDNRA的相对表达量较3xTg组明显下调(P=0.026 7)，提示玛仕度肽可以抑制EDNRA的过表达。说明玛仕度肽可能通过抑制EDNRA过表达治疗阿尔茨海默病，EDNRA可能为玛仕度肽治疗阿尔茨海默病的潜在靶点，后文将围绕此靶点深入探讨。"

References

[1] ZHANG Z, XUE P, BENDLIN BB, et al. Melatonin: a potential nighttime guardian against Alzheimer’s. Mol Psychiatry. 2025;30(1):237-250.
[2] LANE CA, HARDY J, SCHOTT JM, et al. Alzheimer’s disease. Eur J Neurol. 2018; 25(1):59-70.
[3] ZHENG Q, WANG X. Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy. Protein Cell. 2025;16(2):83-120.
[4] HARDY J. Alzheimer’s Disease: Treatment Challenges for the Future. J Neurochem. 2025;169(8):e70176.
[5] WANG R, REDDY PH. Role of Glutamate and NMDA Receptors in Alzheimer’s Disease. J Alzheimers Dis. 2017;57(4):1041-1048.
[6] LIANG Y, DORE V, ROWE CC, et al. Clinical Evidence for GLP-1 Receptor Agonists in Alzheimer’s Disease: A Systematic Review. J Alzheimers Dis Rep. 2024;8(1):777-789.
[7] JI L, JIANG H, BI Y, et al. Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight. N Engl J Med. 2025;392(22):2215-2225.
[8] VARGAS-SORIA M, CARRANZA-NAVAL MJ, DEL MARCO A, et al. Role of liraglutide in Alzheimer’s disease pathology. Alzheimers Res Ther. 2021;13(1):112.
[9] WANG W, WANG Q, QI X, et al. Associations of semaglutide with first-time diagnosis of Alzheimer’s disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US. Alzheimers Dement. 2024; 20(12):8661-8672.
[10] WANG ZJ, LI XR, CHAI SF, et al. Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of Alzheimer’s disease via the GLP-1R/SIRT1/GLUT4 pathway. Neuropharmacology. 2023;240:109716.
[11] SALAMEH TS, RHEA EM, TALBOT K, et al. Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer’s and Parkinson’s disease therapeutics. Biochem Pharmacol. 2020;180:114187.
[12] DONG W, BAI J, YUAN Q, et al. Mazdutide, a dual agonist targeting GLP-1R and GCGR, mitigates diabetes-associated cognitive dysfunction: mechanistic insights from multi-omics analysis. EBioMedicine. 2025;117:105791.
[13] DING K, ZHANG Z, HAN Z, et al. Liver ALKBH5 regulates glucose and lipid homeostasis independently through GCGR and mTORC1 signaling. Science. 2025;387(6737):eadp4120.
[14] ZIMMERMANN T, THOMAS L, BAADER-PAGLER T, et al. BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy. Mol Metab. 2022;66:101633.
[15] PINERO J, SAUCH J, SANZ F, et al. The DisGeNET cytoscape app: Exploring and visualizing disease genomics data. Comput Struct Biotechnol J. 2021;19:2960-2967.
[16] WANG Y, XIAO J, SUZEK TO, et al. PubChem’s BioAssay Database. Nucleic Acids Res. 2012;40(Database issue):D400-D412.
[17] SHANNON P, MARKIEL A, OZIER O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003; 13(11):2498-2504.
[18] CHIN CH, CHEN SH, WU HH, et al. CytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst Biol. 2014;8 Suppl 4(Suppl 4):S11.
[19] CHEN T, SUN T, BIAN Y, et al. The Design and Optimization of Monomeric Multitarget Peptides for the Treatment of Multifactorial Diseases. J Med Chem. 2022;65(5):3685-3705.
[20] BERTONI-FREDDARI C, SENSI SL, GIORGETTI B, et al. Decreased presence of perforated synapses in a triple-transgenic mouse model of Alzheimer’s disease. Rejuvenation Res. 2008;11(2):309-313.
[21] WANG ZJ, HAN WN, CHAI SF, et al. Semaglutide promotes the transition of microglia from M1 to M2 type to reduce brain inflammation in APP/PS1/tau mice. Neuroscience. 2024;563:222-234.
[22] MEKADA K, YOSHIKI A. Substrains matter in phenotyping of C57BL/6 mice. Exp Anim. 2021;70(2):145-160.
[23] CABRAL-MARQUES O, MARQUES A, GIIL LM, et al. GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis. Nat Commun. 2018;9(1):5224.
[24] XU Z, ZHOU Q, LIU C, et al. EDNRA affects susceptibility to large artery atherosclerosis stroke through potential inflammatory pathway. Sci Rep. 2024; 14(1):25173.
[25] WANG M, WANG L, LI X, et al. EDNRA regulates the tumour immune environment and predicts the efficacy and prognosis of cancer immunotherapy. J Cell Mol Med. 2024;28(22):e70172.
[26] LING W, JOHNSON SK, MEHDI SJ, et al. EDNRA-Expressing Mesenchymal Cells are Expanded in Myeloma Interstitial Bone Marrow and Associated with Disease Progression. Cancers (Basel). 2023;15(18):4519.
[27] LEE YJ, JUNG E, CHOI J, et al. The EDN1/EDNRA/beta‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation. Int J Oncol. 2023;62(1):13.
[28] PALMER JC, BARKER R, KEHOE PG, et al. Endothelin-1 is elevated in Alzheimer’s disease and upregulated by amyloid-beta. J Alzheimers Dis. 2012;29(4):853-861.
[29] MINERS JS, PALMER JC, TAYLER H, et al. Abeta degradation or cerebral perfusion? Divergent effects of multifunctional enzymes. Front Aging Neurosci. 2014;6:238.
[30] ZHANG J, WANG YJ, WANG X, et al. PKC-Mediated Endothelin-1 Expression in Endothelial Cell Promotes Macrophage Activation in Atherogenesis. Am J Hypertens. 2019;32(9):880-889.
[31] YANG W, LIU Y, XU QQ, et al. Sulforaphene Ameliorates Neuroinflammation and Hyperphosphorylated Tau Protein via Regulating the PI3K/Akt/GSK-3beta Pathway in Experimental Models of Alzheimer’s Disease. Oxid Med Cell Longev. 2020;2020:4754195.
[32] PAHLAVANI HA. Exercise therapy to prevent and treat Alzheimer’s disease. Front Aging Neurosci. 2023;15:1243869.
[33] RAJABLI F, BENCHEK P, TOSTO G, et al. Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer’s disease. Genome Biol. 2025;26(1):210.
[34] SINGH N, NANDY SK, JYOTI A, et al. Protein Kinase C (PKC) in Neurological Health: Implications for Alzheimer’s Disease and Chronic Alcohol Consumption. Brain Sci. 2024;14(6):554.
[35] VERMA A, CHAUDHARY S, SOLANKI K, et al. Exendin-4: a potential therapeutic strategy for Alzheimer’s disease and Parkinson’s disease. Chem Biol Drug Des. 2024;103(1):e14426.
[36] KANG X, WANG D, ZHANG L, et al. Exendin-4 ameliorates tau hyperphosphorylation and cognitive impairment in type 2 diabetes through acting on Wnt/beta-catenin/NeuroD1 pathway. Mol Med. 2023;29(1):118.
[37] RAJABI H, AHMADI M, ASLANI S, et al. Exendin-4 as a Versatile Therapeutic Agent for the Amelioration of Diabetic Changes. Adv Pharm Bull. 2022;12(2):237-247.
[38] ESPARZA-SALAZAR FJ, LEZAMA-TOLEDO AR, RIVERA-MONROY G, et al. Exendin-4 for Parkinson’s disease. Brain Circ. 2021;7(1):41-43.
[39] WEI R, ZHANG L, HU W, et al. Zeb2/Axin2-Enriched BMSC-Derived Exosomes Promote Post-Stroke Functional Recovery by Enhancing Neurogenesis and Neural Plasticity. J Mol Neurosci. 2022;72(1):69-81.
[40] YANG G, PEI YN, SHAO SJ, et al. [Effects of electroacupuncture at “Baihui” and “Yongquan” on the levels of synaptic plasticity related proteins postsynaptic density-95 and synaptophysin in hippocampus of APP/PS1 mice]. Zhen Ci Yan Jiu. 2020;45(4):310-314.
[41] VE H, CABANA VC, GOUSPILLOU G, et al. Quantitative Immunoblotting Analyses Reveal that the Abundance of Actin, Tubulin, Synaptophysin and EEA1 Proteins is Altered in the Brains of Aged Mice. Neuroscience. 2020;442:100-113.
[42] WANG H, SHEN Z, WU CS, et al. Neuronal ablation of GHSR mitigates diet-induced depression and memory impairment via AMPK-autophagy signaling-mediated inflammation. Front Immunol. 2024;15:1339937.
[43] ZHANG LQ, ZHANG W, LI T, et al. GLP-1R activation ameliorated novel-object recognition memory dysfunction via regulating hippocampal AMPK/NF-kappaB pathway in neuropathic pain mice. Neurobiol Learn Mem. 2021;182:107463.
[44] ZHANG QH, HAO JW, LI GL, et al. Proinflammatory switch from Galphas to Galphai signaling by Glucagon-like peptide-1 receptor in murine splenic monocyte following burn injury. Inflamm Res. 2018;67(2):157-168.
[45] ATEF MM, ABOU HN, HAFEZ YM, et al. The potential protective effect of liraglutide on valproic acid induced liver injury in rats: Targeting HMGB1/RAGE axis and RIPK3/MLKL mediated necroptosis. Cell Biochem Funct. 2023;41(8):1209-1219.
[46] JI L, JIANG H, CHENG Z, et al. A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity. Nat Commun. 2023;14(1):8289.
[47] BHATTACHAR SN, THAM LS, LI Y, et al. Mazdutide reduces body weight in adults with overweight or obesity: a high-dose Phase 1 trial. Diabetes Obes Metab. 2025;27(11):6460-6469.
[48] AYESH H, AYESH S, NISWENDER K. Mazdutide Versus Dulaglutide for Weight Loss and Diabetes Management: Meta-Analysis of Randomized Clinical Trials. Am J Ther. 2024;31(5):e619-e622.
[49] DONG W, BAI J, YUAN Q, et al. Mazdutide, a dual agonist targeting GLP-1R and GCGR, mitigates diabetes-associated cognitive dysfunction: mechanistic insights from multi-omics analysis. EBioMedicine. 2025;117:105791.
[50] JI L, JIANG H, BI Y, et al. Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight. N Engl J Med. 2025;392(22):2215-2225.