{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T23:29:40Z","timestamp":1793316580206,"version":"4.5.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T00:00:00Z","timestamp":1731974400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T00:00:00Z","timestamp":1731974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Brain"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Alzheimer\u2019s disease (AD), an age-related neurodegenerative disorder, is characterized by irreversible brain tissue degeneration. The amyloid-\u03b2 (A\u03b2) cascade hypothesis stands as the predominant paradigm explaining AD pathogenesis. This study aimed to elucidate the mechanisms underlying A\u03b2-induced pyroptosis in AD. AD models were established using amyloid precursor protein\/presenilin 1 (APP\/PS1) transgenic mice and A\u03b2-treated BV-2 cells (5 \u00b5M, 24\u00a0h). NEK7 expression was evaluated in vitro and in vivo. Cell pyroptosis was assessed before and after NEK7 expression was inhibited in BV-2 cells. Adeno-associated virus (AAV) vectors carrying short hairpin RNA (shRNA) against NEK7 (AAV-sh-NEK7) were administered to mice to knockdown NEK7 in vivo. Spatial learning and memory abilities were evaluated using the Morris water maze test. The interaction between NEK7 and histone H4 lysine 12 lactylation (H4K12la) were then investigated. The results suggested that NEK7 expression was markedly elevated in both in vitro and in vivo AD models. Treatment with A\u03b2 significantly reduced cell viability and enhanced pyroptosis in BV-2 cells; these effects were reversed by inhibiting NEK7. Furthermore, AD mice with NEK7 knockdown exhibited shorter escape latencies and increased time spent in the target quadrant, suggesting that NEK7 inhibition improved cognitive function and memory retention. Mechanistically, A\u03b2 treatment induced histone lactylation in BV-2 cells, and suppression of lactylation attenuated NEK7 transcriptional activity and mRNA levels. In summary, elevated NEK7 expression promoted histone lactylation in BV-2 cells, thereby facilitating pyroptosis. Inhibition of NEK7 conferred protection against A\u03b2-induced cellular damage and enhanced cognitive performance and memory retention in AD model mice. Collectively, targeting NEK7 represents a potential therapeutic strategy for alleviating AD symptoms.<\/jats:p>\n                <jats:p><jats:bold>Graphical abstract<\/jats:bold><\/jats:p>","DOI":"10.1186\/s13041-024-01156-9","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T20:09:02Z","timestamp":1732046942000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["NEK7 induces lactylation in Alzheimer\u2019s disease to promote pyroptosis in BV-2 cells"],"prefix":"10.1186","volume":"17","author":[{"given":"Jing","family":"Cheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,19]]},"reference":[{"key":"1156_CR1","doi-asserted-by":"crossref","unstructured":"Haque R, Watson CM, Liu J, Carter EK, Duong DM, Lah JJ et al. A protein panel in cerebrospinal fluid for diagnostic and predictive assessment of Alzheimer\u2019s disease. Sci Transl Med. [Journal Article]. 2023;15(712):g4122.","DOI":"10.1126\/scitranslmed.adg4122"},{"key":"1156_CR2","unstructured":"Sandeep GG, Konduri P, Kolusu AS, Namburi SV, Chunduru B, Nemmani K et al. Neuroprotective Effect of Saroglitazar on Scopolamine-Induced Alzheimer\u2019s in Rats: Insights into the Underlying Mechanisms. ACS Chem Neurosci. [Journal Article]. 2023."},{"key":"1156_CR3","doi-asserted-by":"crossref","unstructured":"Zadka L, Sochocka M, Hachiya N, Chojdak-Lukasiewicz J, Dziegiel P, Piasecki E et al. Endocytosis and Alzheimer\u2019s disease. Geroscience [Journal Article; Review]. 2023.","DOI":"10.1007\/s11357-023-00923-1"},{"key":"1156_CR4","doi-asserted-by":"crossref","unstructured":"Zhang D, Zhang Y, Pan J, Cao J, Sun X, Li X, et al. Degradation of NLRP3 by p62-dependent-autophagy improves cognitive function in Alzheimer\u2019s disease by maintaining the phagocytic function of microglia. CNS Neurosci Ther. 2023:2023\u201301.","DOI":"10.1111\/cns.14219"},{"key":"1156_CR5","doi-asserted-by":"crossref","unstructured":"de Dios C, Abadin X, Roca-Agujetas V, Jimenez-Martinez M, Morales A, Trullas R et al. Inflammasome activation under high cholesterol load triggers a protective microglial phenotype while promoting neuronal pyroptosis. Transl Neurodegener. 2023;12(1):10.","DOI":"10.1186\/s40035-023-00343-3"},{"key":"1156_CR6","doi-asserted-by":"crossref","unstructured":"Wang G, Lin Y, Shen H. Exposure to Polystyrene Microplastics Promotes the Progression of Cognitive Impairment in Alzheimer\u2019s Disease: Association with Induction of Microglial Pyroptosis. Mol Neurobiol. [Journal Article]. 2023.","DOI":"10.1007\/s12035-023-03625-z"},{"key":"1156_CR7","doi-asserted-by":"crossref","unstructured":"Cai Y, Chai Y, Fu Y, Wang Y, Zhang Y, Zhang X et al. Salidroside Ameliorates Alzheimer\u2019s Disease by Targeting NLRP3 Inflammasome-Mediated Pyroptosis. Front Aging Neurosci. 2022;13:809433.","DOI":"10.3389\/fnagi.2021.809433"},{"key":"1156_CR8","doi-asserted-by":"crossref","unstructured":"Sharif H, Wang L, Wang WL, Magupalli VG, Andreeva L, Qiao Q et al. Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome. Nature (London). 2019;570(7761):338\u201343.","DOI":"10.1038\/s41586-019-1295-z"},{"key":"1156_CR9","doi-asserted-by":"crossref","unstructured":"Li Q, Feng H, Wang H, Wang Y, Mou W, Xu G et al. Licochalcone B specifically inhibits the NLRP3 inflammasome by disrupting NEK7-NLRP3 interaction. Embo Rep. 2022;23(2):e53499.","DOI":"10.15252\/embr.202153499"},{"key":"1156_CR10","doi-asserted-by":"crossref","unstructured":"Krauthausen M, Kummer MP, Zimmermann J, Reyes-Irisarri E, Terwel D, Bulic B et al. CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer\u2019s disease model. J Clin Investig. 2015;125(1):365\u201378.","DOI":"10.1172\/JCI66771"},{"key":"1156_CR11","doi-asserted-by":"crossref","unstructured":"Ikram M, Muhammad T, Rehman SU, Khan A, Jo MG, Ali T et al. Hesperetin confers neuroprotection by regulating Nrf2\/TLR4\/NF-\u03baB signaling in an A\u03b2 mouse model. Mol Neurobiol. 2019;56(9):6293\u2013309.","DOI":"10.1007\/s12035-019-1512-7"},{"key":"1156_CR12","doi-asserted-by":"crossref","unstructured":"Huang Z, Ji H, Shi J, Zhu X, Zhi Z. Engeletin attenuates A\u03b21\u201342-Induced oxidative stress and neuroinflammation by Keap1\/Nrf2 pathway. 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Influenza a viruses limit NLRP3-NEK7\u2010complex formation and pyroptosis in human macrophages. EMBO Rep. 2020;21(12):e50421.","DOI":"10.15252\/embr.202050421"}],"container-title":["Molecular Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-024-01156-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13041-024-01156-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-024-01156-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T21:21:20Z","timestamp":1732051280000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecularbrain.biomedcentral.com\/articles\/10.1186\/s13041-024-01156-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,19]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["1156"],"URL":"https:\/\/doi.org\/10.1186\/s13041-024-01156-9","relation":{},"ISSN":["1756-6606"],"issn-type":[{"value":"1756-6606","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,19]]},"assertion":[{"value":"31 July 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 November 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 November 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was approved by the Ethics Committee of Tongren Hospital, Shanghai Jiao Tong University School of Medicine. All experiments were performed in accordance with the ARRIVE guidelines.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All authors approved the final manuscript and the submission to this journal.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors confirm that no conflicts of interest exist in this work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"81"}}