2. Academic Validation
  3. H4K12 lactylation-regulated NLRP3 is involved in cigarette smoke-accelerated Alzheimer-like pathology through mTOR-regulated autophagy and activation of microglia

H4K12 lactylation-regulated NLRP3 is involved in cigarette smoke-accelerated Alzheimer-like pathology through mTOR-regulated autophagy and activation of microglia

  • J Hazard Mater. 2025 Jan 21:488:137310. doi: 10.1016/j.jhazmat.2025.137310.
Hailan Wang 1,  Haibo Xia 1,  Jun Bai 2,  Zhongyue Wang 1,  Yue Wang 1,  Jiaheng Lin 1,  Cheng Cheng 1,  Weiyong Chen 1,  Jingshu Zhang 3,  Qingbi Zhang 4,  Qizhan Liu 5
Affiliations

Affiliations

  • 1 The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China; Center for Global Health, China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China.
  • 2 Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou 646000, Sichuan, PR China.
  • 3 The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China.
  • 4 Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou 646000, Sichuan, PR China. Electronic address: qingbizhang@126.com.
  • 5 The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Suzhou Institute for Advanced Study of Public Health, Gusu School, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China; Center for Global Health, China International Cooperation Center for Environment and Human Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China. Electronic address: drqzliu@hotmail.com.
PMID: 39862777 DOI: 10.1016/j.jhazmat.2025.137310
Abstract

Cigarette smoke (CS), an indoor environmental pollution, is an environmental risk factor for diverse neurological disorders. However, the neurotoxicological effects and mechanisms of CS on Alzheimer's disease (AD) progression remain unclear. We found that CS accelerated the progression of AD, including increasing β-amyloid (Aβ) plaque deposition and exacerbating cognitive decline. Mechanistically, CS exposure increased the levels of NOD-like Receptor protein 3 (NLRP3), which impaired autophagic flux in microglia by activating the mammalian target of rapamycin (mTOR) signal. Metabolomics analysis revealed an upregulation of lactate levels and an increase in global protein lysine lactylation in the brain tissue of CS-exposed AD-transgenic mice. Immunoprecipitation-Mass Spectrometry and chromatin immunoprecipitation assays demonstrated that CS elevates H4K12 lactylation (H4K12la) levels, which accumulate at the promoter region of NLRP3, leading to the activation of its transcription. Via inhibiting lactate or NLRP3 activation, oxamate and MCC950 alleviates these CS-induced effects. Therefore, our data suggest that the CS-induced increase in lactate levels triggers NLRP3 transcriptional activation through H4K12la, which subsequently leads to mTOR-mediated Autophagy dysfunction in microglia, promoting microglial activation and resulting in Aβ plaque accumulation in AD-transgenic mice. This provides a new mechanism and potential therapeutic target for AD associated with environmental factors.

Keywords

Alzheimer's disease; Cigarette smoke; Lactylation; Microglial autophagy; NLRP3/mTOR axis.

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