{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T01:24:09Z","timestamp":1789694649737,"version":"4.0.1"},"reference-count":25,"publisher":"IMR Press","issue":"10","license":[{"start":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T00:00:00Z","timestamp":1729468800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Interdisciplinary Program of Shanghai Jiao Tong University","award":["YG2021QN89"],"award-info":[{"award-number":["YG2021QN89"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Integr. Neurosci."],"abstract":"<jats:p>Purpose: Alzheimer\u2019s disease (AD) is characterized by cognitive decline and abnormal protein accumulation. Copper imbalance and pyroptosis play significant roles in the pathogenesis of AD. Recent studies have suggested that dysregulated copper homeostasis contributed to \u03b2-amyloid accumulation, which may activate the NOD-like receptor protein 3 (NLRP3)-related pyroptosis pathway, promoting neuronal damages and AD progression. Therefore, the present study aims to investigates whether copper facilitates AD through exacerbating \u03b2-amyloid (A\u03b2) induced activation of NLRP3\/Caspase-1\/Gasdermin D (GSDMD)-mediated neuronal cell pyroptosis. Methods: Mouse hippocampal HT-22 cells were cultured with A\u03b21-42 oligomer for 24 h as AD Model group. CuCl2 treatment was administered to the AD cell model, and cell survivability levels were detected by Cell Counting Kit-8 (CCK-8), TdT-mediated dUTP nick end labeling (TUNEL), and other relevant kits. Mitochondrial function was evaluated using Mitochondrial membrane potential dye JC-1 and transmission electron microscopy (TEM). After intervention with the NLRP3 inhibitor MCC950, activation of the NLRP3\/Caspase-1\/GSDMD pathway by copper ions (Cu2+) was confirmed via Western Blot. Thioredoxin T (ThT) fluorescence assay was performed to observe the aggregation effect of A\u03b2 induced by Cu2+ overload. Results: CuCl2 treatment of the AD cell model resulted in up-regulation of the levels of Lactate Dehydrogenase (LDH), Interleukin-1\u03b2 (IL-1\u03b2), and IL-18 expression, which indicated activation of pyroptosis. We observed a significant decrease in mitochondrial membrane potential, mitochondrial swelling, and loss of mitochondrial cristae by fluorescence microscopy and TEM. ThT fluorescence imaging showed that Cu2+ promoted A\u03b2 aggregation and up-regulated NLRP3, apoptosis-associated speck-like protein containing a CARD (ACS), Caspase-1, Cleaved Caspase-1, GSDMD, and Gasdermin D N-terminal (GSDMD-NT). The NLRP3 inhibitor MCC950 partially reversed Cu2+-mediated pyroptosis in HT-22 cells. Conclusions: Exposure to copper ions disrupt mitochondrial copper homeostasis, promotes A\u03b2 aggregation, and activates NLRP3 inflammasomes, further promoting the A\u03b2 aggregation activated pyroptosis in AD cell models.<\/jats:p>","DOI":"10.31083\/j.jin2310194","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T20:49:41Z","timestamp":1730234981000},"source":"Crossref","is-referenced-by-count":26,"title":["Copper Overload Promotes \u03b2-amyloid Induced NLRP3\/Caspase-1\/GSDMD-Mediated Pyroptosis in Alzheimer\u2019s Disease"],"prefix":"10.31083","volume":"23","author":[{"given":"Min-Juan","family":"Zhu","sequence":"first","affiliation":[{"name":"Neurology Department, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhang","sequence":"first","affiliation":[{"name":"Neurology Department, Shanghai Xuhui Central Hospital, 200041 Shanghai, China"},{"name":"Neurology Department, Zhongshan-Xuhui Hospital, Fudan University, 200437 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Peng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurovascular Intervention, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2024,10,21]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Scheltens P, De Strooper B, Kivipelto M, Holstege H, Ch\u00e9telat G, Teunissen CE, et al. Alzheimer\u2019s disease. Lancet. 2021; 397: 1577\u20131590.","DOI":"10.1016\/S0140-6736(20)32205-4"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"Yin JT, Xu XW, Jin CY, Yuan XY, Wang XG. The Influence of the Gut Microbiota on Alzheimer\u2019s Disease: A Narrative Review. Journal of Integrative Neuroscience. 2023; 22: 38.","DOI":"10.31083\/j.jin2202038"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"Tiwari S, Atluri V, Kaushik A, Yndart A, Nair M. Alzheimer\u2019s disease: pathogenesis, diagnostics, and therapeutics. International Journal of Nanomedicine. 2019; 14: 5541\u20135554.","DOI":"10.2147\/IJN.S200490"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"Chen G, Han M, Chen Y, Lei Y, Li M, Wang L, et al. Danggui-Shaoyao-San Promotes Amyloid-\u03b2 Clearance through Regulating Microglia Polarization via Trem2 in BV2 Cells. Journal of Integrative Neuroscience. 2023; 22: 72.","DOI":"10.31083\/j.jin2203072"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"Ruiz LM, Libedinsky A, Elorza AA. Role of Copper on Mitochondrial Function and Metabolism. Frontiers in Molecular Biosciences. 2021; 8: 711227.","DOI":"10.3389\/fmolb.2021.711227"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"Tassone G, Kola A, Valensin D, Pozzi C. Dynamic Interplay between Copper Toxicity and Mitochondrial Dysfunction in Alzheimer\u2019s Disease. Life. 2021; 11: 386.","DOI":"10.3390\/life11050386"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"Sensi SL, Granzotto A, Siotto M, Squitti R. Copper and Zinc Dysregulation in Alzheimer\u2019s Disease. Trends in Pharmacological Sciences. 2018; 39: 1049\u20131063.","DOI":"10.1016\/j.tips.2018.10.001"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"Li X, Chen X, Gao X. Copper and cuproptosis: new therapeutic approaches for Alzheimer\u2019s disease. Frontiers in Aging Neuroscience. 2023; 15: 1300405.","DOI":"10.3389\/fnagi.2023.1300405"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"Singh SK, Balendra V, Obaid AA, Esposto J, Tikhonova MA, Gautam NK, et al. Copper-mediated \u03b2-amyloid toxicity and its chelation therapy in Alzheimer\u2019s disease. Metallomics: Integrated Biometal Science. 2022; 14: mfac018.","DOI":"10.1093\/mtomcs\/mfac018"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"Stancu IC, Cremers N, Vanrusselt H, Couturier J, Vanoosthuyse A, Kessels S, et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathologica. 2019; 137: 599\u2013617.","DOI":"10.1007\/s00401-018-01957-y"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"Zhang Y, Gao H, Zheng W, Xu H. Current understanding of the interactions between metal ions and Apolipoprotein E in Alzheimer\u2019s disease. Neurobiology of Disease. 2022; 172: 105824.","DOI":"10.1016\/j.nbd.2022.105824"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"Yu P, Zhang X, Liu N, Tang L, Peng C, Chen X. Pyroptosis: mechanisms and diseases. Signal Transduction and Targeted Therapy. 2021; 6: 128.","DOI":"10.1038\/s41392-021-00507-5"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"Moonen S, Koper MJ, Van Schoor E, Schaeverbeke JM, Vandenberghe R, von Arnim CAF, et al. Pyroptosis in Alzheimer\u2019s disease: cell type-specific activation in microglia, astrocytes and neurons. Acta Neuropathologica. 2023; 145: 175\u2013195.","DOI":"10.1007\/s00401-022-02528-y"},{"key":"ref14","doi-asserted-by":"crossref","unstructured":"Chen WP, Zhang G, Cheng ZJ, Gu XH, Li M, Liu X. Inhibitor Kappa B Kinase \u03b2, Modulated by DJ-1\/p-VHL, Reduces Phosphorylated Tau (p-Tau) Accumulation via Autophagy in Alzheimer\u2019s Disease Model. Neuroscience. 2021; 452: 1\u201312.","DOI":"10.1016\/j.neuroscience.2020.10.005"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"Shi W, Zhang H, Zhang Y, Lu L, Zhou Q, Wang Y, et al. Co-exposure to Fe, Zn, and Cu induced neuronal ferroptosis with associated lipid metabolism disorder via the ERK\/cPLA2\/AA pathway. Environmental Pollution. 2023; 336: 122438.","DOI":"10.1016\/j.envpol.2023.122438"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"Lu Q, Zhang Y, Zhao C, Zhang H, Pu Y, Yin L. Copper induces oxidative stress and apoptosis of hippocampal neuron via pCREB\/BDNF\/ and Nrf2\/HO-1\/NQO1 pathway. Journal of Applied Toxicology. 2022; 42: 694\u2013705.","DOI":"10.1002\/jat.4252"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"Cilliers K. Trace element alterations in Alzheimer\u2019s disease: A review. Clinical Anatomy. 2021; 34: 766\u2013773.","DOI":"10.1002\/ca.23727"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"Patel R, Aschner M. Commonalities between Copper Neurotoxicity and Alzheimer\u2019s Disease. Toxics. 2021; 9: 4.","DOI":"10.3390\/toxics9010004"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"Gromadzka G, Tarnacka B, Flaga A, Adamczyk A. Copper Dyshomeostasis in Neurodegenerative Diseases-Therapeutic Implications. International Journal of Molecular Sciences. 2020; 21: 9259.","DOI":"10.3390\/ijms21239259"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"Squitti R, Lupoi D, Pasqualetti P, Dal Forno G, Vernieri F, Chiovenda P, et al. Elevation of serum copper levels in Alzheimer\u2019s disease. Neurology. 2002; 59: 1153\u20131161.","DOI":"10.1212\/WNL.59.8.1153"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"An Y, Li S, Huang X, Chen X, Shan H, Zhang M. The Role of Copper Homeostasis in Brain Disease. International Journal of Molecular Sciences. 2022; 23: 13850.","DOI":"10.3390\/ijms232213850"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"Zhu X, Liu W, Zhao W, Chang Z, Yang J. The co-effect of copper and lipid vesicles on A\u03b2 aggregation. Biochimica et Biophysica Acta. Biomembranes. 2023; 1865: 184082.","DOI":"10.1016\/j.bbamem.2022.184082"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"Omar SH, Scott CJ, Hamlin AS, Obied HK. Olive Biophenols Reduces Alzheimer\u2019s Pathology in SH-SY5Y Cells and APPswe Mice. International Journal of Molecular Sciences. 2018; 20: 125.","DOI":"10.3390\/ijms20010125"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"Dong J, Wang X, Xu C, Gao M, Wang S, Zhang J, et al. Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson\u2019s disease. Cell Death & Disease. 2021; 12: 87.","DOI":"10.1038\/s41419-021-03397-1"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"Zhu X, Hao W, Liu Z, Song Y, Hao C, Wu S, et al. Aluminum induces neuroinflammation via P2X7 receptor activating NLRP3 inflammasome pathway. Ecotoxicology and Environmental Safety. 2023; 249: 114373.","DOI":"10.1016\/j.ecoenv.2022.114373"}],"container-title":["Journal of Integrative Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/JIN\/23\/10\/10.31083\/j.jin2310194","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T11:37:41Z","timestamp":1732707461000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/JIN\/23\/10\/10.31083\/j.jin2310194"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,21]]},"references-count":25,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2024]]}},"alternative-id":["S0219-6352(24)00811-8"],"URL":"https:\/\/doi.org\/10.31083\/j.jin2310194","relation":{},"ISSN":["0219-6352","1757-448X"],"issn-type":[{"value":"0219-6352","type":"print"},{"value":"1757-448X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,21]]},"article-number":"194"}}