Xie Jun, Cao Kai, Liu Luman, Zhang Liding, Yang Ying, Gong Hui, Luo Haiming
MOE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China.
State Key Laboratory of Digital Medical Engineering, Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou 570228, China.
Theranostics. 2025 Jun 20;15(15):7467-7488. doi: 10.7150/thno.112213. eCollection 2025.
Evidence shows that neuroinflammation mediated by microglial activation plays an important role in Alzheimer's disease (AD) pathogenesis. However, the relationship between microglial phenotype and fibrillar β-amyloid (fAβ) pathology in anti-inflammatory treatment of AD remains unclear. We designed a water-soluble MnO nanozymes and demonstrated its ability to reverse lipopolysaccharide (LPS)-induced microglial transition from M1 to M2 phenotype by clearing reactive oxygen species (ROS). In 5×FAD transgenic mice, intranasal (IN) instillation of MnO nanozymes initially promoted M2 microglial polarization and significantly reduced neuroinflammation after 4 weeks of treatment. After 8 weeks of continuous treatment, they further alleviate fAβ pathology and improved learning and memory deficits in 5×FAD mice. The excellent anti-inflammatory effect of MnO nanozymes is achieved by inhibiting the Toll-like receptor 4 (TLR4)/nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase isoform 2 (NOX2) pathway to clear ROS. This study reveals the molecular mechanism of MnO nanozymes modulating microglia phenotype to attenuate neuroinflammation primarily through inhibition of the TLR4/NOX2 pathway and highlights the temporal sequence of anti-inflammatory treatment in regulating microglial phenotype and improving fAβ pathology, providing new insights for the anti-inflammatory treatment of AD and other neurological diseases.
证据表明，小胶质细胞激活介导的神经炎症在阿尔茨海默病（AD）发病机制中起重要作用。然而，在AD的抗炎治疗中，小胶质细胞表型与纤维状β-淀粉样蛋白（fAβ）病理之间的关系仍不清楚。我们设计了一种水溶性MnO纳米酶，并证明其能够通过清除活性氧（ROS）来逆转脂多糖（LPS）诱导的小胶质细胞从M1型向M2型的转变。在5×FAD转基因小鼠中，经鼻（IN）滴注MnO纳米酶最初促进了M2小胶质细胞极化，并在治疗4周后显著减轻了神经炎症。连续治疗8周后，它们进一步减轻了5×FAD小鼠的fAβ病理，并改善了学习和记忆缺陷。MnO纳米酶优异的抗炎作用是通过抑制Toll样受体4（TLR4）/烟酰胺腺嘌呤二核苷酸磷酸（NAPDH）氧化酶亚型2（NOX2）途径来清除ROS实现的。本研究揭示了MnO纳米酶调节小胶质细胞表型以减轻神经炎症的分子机制，主要是通过抑制TLR4/NOX2途径，并突出了抗炎治疗在调节小胶质细胞表型和改善fAβ病理方面的时间顺序，为AD和其他神经疾病的抗炎治疗提供了新的见解。
