Alzheimer's disease (AD) is a pathology characterized by the abnormal accumulation of amyloid-beta (Aβ) and hyperphosphorylated tau. Oxidative stress and neuroinflammation are also strongly related to this disease. The ability of two new glycosylated angucyclinones, streptocyclinones A and B (1 and 2), isolated from Streptomyces sp to improve AD hallmarks was evaluated. Compounds were able to protect SH-SY5Y neuroblastoma cells from H₂O₂-induced oxidative injury by activating the nuclear factor E2-related factor (Nrf2). Their capacity to modulate neuroinflammation was tested in lipopolysaccharide-activated BV2 microglial cells. Compounds reduced the release of pro-inflammatory factors, inhibited the activation of NFκB and mitogen activated kinases (MAPK), and induced the translocation of Nrf2 to the nucleus of microglial cells. A trans-well co-culture was established to determine the effect of microglia treated with streptocyclinones on the survival of SH-SY5Y cells. The cell viability of neuroblastoma cells increased when the compounds were added to BV2 cells. SH-SY5Y-TMHT441 cells were used to determine the effect of compounds on tau phosphorylation. Both compounds reduced tau hyperphophorylation by targeting MAPK kinases. Moreover, streptocyclinone B (2) was able to inhibit the activity of β-secretase 1 and decrease the release of reactive oxygen species in BV2 cells stimulated with Aβ. With the same co-culture trans-well system, the treatment of Aβ-stimulated microglia with compound 2 augmented the viability of SH-SY5Y-TMHT441 cells. The results presented in this work provide evidences of the multitarget activities displayed by these new Streptomyces compounds, making them good candidates for further studies in the treatment of AD.

阿尔茨海默氏病（AD）是一种以β-淀粉样蛋白（Aβ）和过度磷酸化的tau蛋白异常积累为特征的病理学。氧化应激和神经炎症也与这种疾病密切相关。评估了从链霉菌属中分离出的两个新的糖基化的古环素酮，链环素酮A和B（1和2）改善AD标记的能力。化合物能够保护SH-SY5Y神经母细胞瘤细胞免受H ₂ O ₂侵害激活核因子E2相关因子（Nrf2）引起的氧化损伤。在脂多糖激活的BV2小胶质细胞中测试了它们调节神经炎症的能力。化合物可减少促炎因子的释放，抑制NFκB和有丝分裂原激活的激酶（MAPK）的活化，并诱导Nrf2易位至小胶质细胞核。建立了跨孔共培养物，以确定用链环蛋白环素处理的小胶质细胞对SH-SY5Y细胞存活的影响。当将化合物添加到BV2细胞中时，神经母细胞瘤细胞的细胞生存力增加。SH-SY5Y-TMHT441细胞用于确定化合物对tau磷酸化的影响。两种化合物都通过靶向MAPK激酶来减少tau过度磷酸化。此外，链霉素B（2）能够抑制β-分泌酶1的活性并减少Aβ刺激的BV2细胞中活性氧的释放。在相同的共培养孔系统中，用化合物2处理Aβ刺激的小胶质细胞可增强SH-SY5Y-TMHT441细胞的活力。这项工作中提出的结果提供了这些新链霉菌化合物显示的多靶标活性的证据，使其成为进一步治疗AD的良好候选者。