Abstract：
Alzheimer\'s disease (AD) is a multifactorial neurodegenerative disorder associated with the amyloid beta (Aβ) and tau hallmarks. The molecular insights into how neuroinflammation is initially triggered and how it affects neuronal cells are yet at the age of infancy. In this study, SH-SY5Y cells were used as a model for neurons by differentiating and were co-cultured with differentiated THP1 cells (microglia model) as well as treated with Aβ(25-35) and with antioxidant FA to study inflammatory, oxidative stress responses and their effects on co-cultured neurons. Neurons co-cultured with microglial cells showed pronounced increase in ROS levels, NOS expression, truncated N-terminal form (34 kDa) of APE1 expression and AIF\'s translocation in the nucleus. The pre-treatment of FA, on the other hand reversed these effects. It was further evaluated how FA/Aβ treatment altered microglial phenotype that in turn affected the neurons. Microglial cells showed M1 phenotype upon Aβ(25-35) stress, while FA induced M2 phenotype against Aβ stress, suggesting that FA alleviated Aβ induced phenotype and its associated effects in the co-cultured neurons by altering the phenotype of microglial cells and induced expression of full length (37 kDa) APE1 enzyme and inhibiting AIF\'s nuclear translocation, thus inhibiting apoptosis. This is the first study that revealed Aβ induced cleavage of APE1 enzyme in differentiated neurons, suggesting that APE1 may be the potential early target of Aβ that loses its function and exacerbates AD pathology. FA activated a fully functional form of APE1 against Aβ stress. The impaired function of APE1 could be the initial mechanism by which Aβ induces oxidative and inflammatory responses and dietary phytochemical FA can be a potential therapeutic strategy in managing the disease by activating APE1 that not only repairs oxidative DNA base damage but also maintains mitochondrial function and alleviates neuroinflammatory responses.
摘要：
阿尔茨海默病（AD）是一种与淀粉样β（Aβ）和tau标志相关的多因素神经退行性疾病。关于神经炎症最初是如何触发的以及它如何影响神经元细胞的分子见解还处于婴儿期。在这项研究中,SH-SY5Y细胞通过分化作为神经元模型，并与分化的THP1细胞共培养（小胶质细胞模型）以及用Aβ（25-35）和抗氧化剂FA处理以研究炎症，氧化应激反应及其对共培养神经元的影响。与小胶质细胞共培养的神经元显示ROS水平显著增加，NOS表达，APE1表达的N末端截短形式(34kDa)和AIF在细胞核中的易位。FA的预处理，另一方面扭转了这些影响。进一步评估了FA/Aβ治疗如何改变小胶质细胞表型,进而影响神经元。小胶质细胞在Aβ（25-35）应激时显示M1表型，而FA诱导M2表型对抗Aβ应激，提示FA通过改变小胶质细胞的表型和诱导全长（37kDa）APE1酶的表达和抑制AIF的核易位来减轻共培养神经元中Aβ诱导的表型及其相关作用，从而抑制细胞凋亡。这是首次揭示Aβ诱导分化神经元中APE1酶裂解的研究，提示APE1可能是Aβ的潜在早期靶标，其功能丧失并加剧AD病理。FA针对Aβ应激激活了APE1的全功能形式。APE1的功能受损可能是Aβ诱导氧化和炎症反应的初始机制，饮食植物化学FA可能是通过激活APE1来管理疾病的潜在治疗策略，APE1不仅可以修复氧化DNA碱基损伤，还可以维持线粒体功能并减轻神经炎症反应。
