Verma Ambika, Azhar Gohar, Patyal Pankaj, Zhang Xiaomin, Wei Jeanne Y
Donald W. Reynolds Department of Geriatrics and Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Cells. 2025 May 30;14(11):804. doi: 10.3390/cells14110804.
Chronic periodontitis, driven by the keystone pathogen , has been increasingly associated with Alzheimer's disease (AD) and AD-related dementias (ADRDs). However, the mechanisms through which -lipopolysaccharide (LPS)-induced release of neuroinflammatory proteins contribute to the pathogenesis of AD and ADRD remain inadequately understood. Caspase-4, a critical mediator of neuroinflammation, plays a pivotal role in these processes following exposure to -LPS. In this study, we investigated the mechanistic role of caspase-4 in -LPS-induced IL-1β production, neuroinflammation, oxidative stress, and mitochondrial alterations in human neuronal and microglial cell lines. Silencing of caspase-4 significantly attenuated IL-1β secretion by inhibiting the activation of the caspase-4-NLRP3-caspase-1-gasdermin D inflammasome pathway, confirming its role in neuroinflammation. Moreover, caspase-4 silencing reduced the activation of amyloid precursor protein and presenilin-1, as well as the secretion of amyloid-β peptides, suggesting a role for caspase-4 in amyloidogenesis. Caspase-4 inhibition also restored the expression of key neuroinflammatory markers, such as total tau, VEGF, TGF, and IL-6, highlighting its central role in regulating neuroinflammatory processes. Furthermore, caspase-4 modulated oxidative stress by regulating reactive oxygen species production and reducing oxidative stress markers like inducible nitric oxide synthase and 4-hydroxynonenal. Additionally, caspase-4 influenced mitochondrial membrane potential, mitochondrial biogenesis, fission, fusion, mitochondrial respiration, and ATP production, all of which were impaired by -LPS but restored with caspase-4 inhibition. These findings provide novel insights into the role of caspase-4 in -LPS-induced neuroinflammation, oxidative stress, and mitochondrial dysfunction, demonstrating caspase-4 as a potential therapeutic target for neurodegenerative conditions associated with AD and related dementias.
由关键病原体驱动的慢性牙周炎与阿尔茨海默病（AD）及AD相关痴呆（ADRDs）的关联日益密切。然而，脂多糖（LPS）诱导神经炎症蛋白释放从而促进AD和ADRD发病机制仍未得到充分理解。半胱天冬酶-4是神经炎症的关键介质，在暴露于LPS后这些过程中起关键作用。在本研究中，我们调查了半胱天冬酶-4在LPS诱导人神经元和小胶质细胞系中白细胞介素-1β产生、神经炎症、氧化应激及线粒体改变中的机制性作用。半胱天冬酶-4沉默通过抑制半胱天冬酶-4-NLRP3-半胱天冬酶-1- Gasdermin D炎性小体途径的激活显著减弱白细胞介素-1β分泌，证实其在神经炎症中的作用。此外，半胱天冬酶-4沉默降低了淀粉样前体蛋白和早老素-1的激活以及淀粉样β肽的分泌，提示半胱天冬酶-4在淀粉样蛋白生成中的作用。半胱天冬酶-4抑制还恢复了关键神经炎症标志物如总tau、血管内皮生长因子、转化生长因子和白细胞介素-6的表达，突出其在调节神经炎症过程中的核心作用。此外，半胱天冬酶-4通过调节活性氧产生和减少诱导型一氧化氮合酶和4-羟基壬烯醛等氧化应激标志物来调节氧化应激。另外，半胱天冬酶-4影响线粒体膜电位、线粒体生物发生、裂变、融合、线粒体呼吸和ATP产生，所有这些在LPS作用下均受损，但通过半胱天冬酶-4抑制得以恢复。这些发现为半胱天冬酶-4在LPS诱导的神经炎症、氧化应激和线粒体功能障碍中的作用提供了新见解，表明半胱天冬酶-4是与AD及相关痴呆相关神经退行性疾病的潜在治疗靶点。
