Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China.
Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, 210009, China.
Food Chem Toxicol. 2022 Aug;166:113227. doi: 10.1016/j.fct.2022.113227. Epub 2022 Jun 10.
Silver nanoparticles (AgNPs) could accumulate in the central nervous system (CNS) and induce neurotoxicity for their widespread use in industry and medicine. Mitochondria are vulnerable to toxicity of AgNPs, however, their role in the neurotoxicity remains unclear. This study aimed to evaluate AgNPs-induced synaptic degeneration in mouse hippocampal neurons (at a dose of 12-120 mg/kg BW via intravenous injection), and to further investigate mechanism of mitophagy, mitochondrial biogenesis process in the neurotoxicity. The results indicated that AgNPs accumulated in mouse hippocampal neurons and induced neurological deficits of learning and memory, which involved in synaptic degeneration accompanied with mitochondrial damage. Mechanistically, AgNPs exposure increased protein expression of PTEN-induced kinase 1 (PINK1), Parkin and inhibited peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1α) protein expression, caused disturbed mitophagy and mitochondrial biogenesis. AgNPs also induced synaptic damage by increasing the protein expression of synaptophysin and decreasing PSD95, MAP2 protein expression. AgNPs exposure even promoted protein expression of amyloid precursor protein (APP) using in amyloid-β (Aβ) cleavage. Furthermore, AgNPs induced hippocampal neuronal synaptic degeneration, mitophagy and mitochondrial biogenesis is dependent on particle-specific AgNPs rather than released silver ions. Our research could provide insights into the regulatory mechanisms of AgNPs-induced neurotoxicity. This study will shed the light of neurotoxicological evaluation of nanoparticles and possible early warning of biomedical applications.
银纳米粒子（AgNPs）由于在工业和医学领域的广泛应用而可能在中枢神经系统（CNS）中积累并诱导神经毒性。线粒体易受到 AgNPs 的毒性影响，然而，其在神经毒性中的作用尚不清楚。本研究旨在评估 AgNPs 在小鼠海马神经元中的突触退化作用（通过静脉注射剂量为 12-120mg/kgBW），并进一步研究自噬、线粒体生物发生过程在神经毒性中的作用机制。结果表明，AgNPs 在小鼠海马神经元中积累并诱导学习和记忆的神经功能缺损，涉及到突触退化和线粒体损伤。从机制上讲，AgNPs 暴露增加了 PTEN 诱导的激酶 1（PINK1）、Parkin 的蛋白表达，抑制了过氧化物酶体增殖物激活受体共激活因子 1α（PGC-1α）蛋白表达，导致线粒体自噬和生物发生失调。AgNPs 还通过增加突触小体蛋白的表达和减少 PSD95、MAP2 蛋白的表达来诱导突触损伤。AgNPs 暴露甚至通过促进淀粉样前体蛋白（APP）的蛋白表达来促进淀粉样β（Aβ）的裂解。此外，AgNPs 诱导的海马神经元突触退化、自噬和线粒体生物发生依赖于颗粒特异性的 AgNPs，而不是释放的银离子。我们的研究为 AgNPs 诱导的神经毒性的调控机制提供了新的认识。这项研究将为纳米颗粒的神经毒理学评价和生物医学应用的早期预警提供新的思路。
