Tang Chong, Wang Jing, Ge Minglei, Fu Li, Huang Jiayue, Yadav Hanshika, Shi Jianhua, Feng Shichun, Wu Feng
Department of General Surgery, Nantong First People's Hospital, Affiliated Hospital 2 of Nantong University, Nantong, China; Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226019, Jiangsu, China.
Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226019, Jiangsu, China.
Int Immunopharmacol. 2025 May 16;155:114666. doi: 10.1016/j.intimp.2025.114666. Epub 2025 Apr 13.
Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid plaques and neuroinflammation, which collectively result in cognitive decline. Peripheral inflammation, particularly intestinal inflammation, has been implicated in exacerbating AD pathology via the gut-brain axis. This study investigated the effects of dextran sulfate sodium (DSS)-induced colitis on amyloid-beta (Aβ) pathology, synaptic integrity, and cognitive function in 5xFAD mice, and explored the roles of neutrophil elastase (NE) and Cathepsin B in these processes. DSS-induced colitis significantly worsened Aβ pathology, evidenced by increased Aβ plaque deposition and elevated soluble Aβ levels in the brain of 5xFAD mice. The inflammatory state triggered extensive neutrophil infiltration and elevated NE levels in the hippocampus, which were closely associated with Cathepsin B activation. This enzymatic cascade is associated with synaptic damage and cognitive deficits. Treatment with the NE inhibitor Sivelestat effectively suppressed NE-mediated Cathepsin B activation, reduced Aβ pathology, restored dendritic spine density, and improved cognitive performance. Additionally, the Cathepsin B inhibitor CA-074 methyl ester (CA-074Me) mitigated the adverse effects of DSS-induced colitis, further emphasizing the role of Cathepsin B in mediating inflammation-driven AD pathology. These findings reveal that the NE-Cathepsin B axis links peripheral inflammation to exacerbated Aβ pathology, synaptic damage, and cognitive impairment, underscoring the potential of targeting NE and Cathepsin B as therapeutic strategies for inflammation-driven AD progression.
阿尔茨海默病（AD）是痴呆的主要病因，其特征为淀粉样斑块和神经炎症，这些共同导致认知能力下降。外周炎症，尤其是肠道炎症，已被认为可通过肠-脑轴加剧AD病理变化。本研究调查了葡聚糖硫酸钠（DSS）诱导的结肠炎对5xFAD小鼠淀粉样β蛋白（Aβ）病理、突触完整性和认知功能的影响，并探讨了中性粒细胞弹性蛋白酶（NE）和组织蛋白酶B在这些过程中的作用。DSS诱导的结肠炎显著恶化了Aβ病理变化，5xFAD小鼠大脑中Aβ斑块沉积增加和可溶性Aβ水平升高证明了这一点。炎症状态引发了广泛的中性粒细胞浸润以及海马中NE水平升高，这与组织蛋白酶B的激活密切相关。这种酶促级联反应与突触损伤和认知缺陷有关。用NE抑制剂西维来司他治疗可有效抑制NE介导的组织蛋白酶B激活，减少Aβ病理变化，恢复树突棘密度，并改善认知表现。此外，组织蛋白酶B抑制剂CA-074甲酯（CA-074Me）减轻了DSS诱导的结肠炎的不良影响，进一步强调了组织蛋白酶B在介导炎症驱动的AD病理变化中的作用。这些发现表明，NE-组织蛋白酶B轴将外周炎症与加剧的Aβ病理变化、突触损伤和认知障碍联系起来，突出了将NE和组织蛋白酶B作为炎症驱动的AD进展治疗策略的潜力。
