Secoisolariciresinol diglucoside ameliorates Alzheimer-like lesions by increasing MKP-1

BackgroundSecoisolariciresinol diglucoside (SDG), a phytoestrogen, has been demonstrated to exert anti-inflammatory and neuroprotective effects. Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) serves as a critical negative regulator of MAPK signaling pathways, and the MAPK signaling pathways play a significant role in the pathogenesis of Alzheimer's disease (AD). However, it remains unclear whether SDG ameliorates Alzheimer-like lesions by regulating the MAPK pathway through increasing MKP-1.ObjectiveWe aimed to investigate the impact of SDG on the Alzheimer-like lesions of AD mice and its mechanisms.MethodsThree-month-old 5×FAD mice were treated with SDG (50 mg·kg-1·d-1, i.g.) for 2 months. Learning and spatial memory function was assessed with the behavioral test. Immunofluorescence and Thioflavine-S staining was assessed with the levels of amyloid-β (Aβ) plaques in the cortex and hippocampus. Western blot was performed to evaluate the level of learning memory-related proteins, hyperphosphorylated tau, APP-related proteins, and MAPK phosphorylation. Besides, knockdown of MKP-1 in N2A/APP cells to investigate whether SDG regulates the MAPK signaling pathway by increasing MKP-1.ResultsWe found that SDG significantly enhanced learning and spatial memory while recovering PSD95, PKA-Cα, and synaptophysin levels in 5×FAD mice. SDG reduced Aβ plaques, tau phosphorylation at Ser 199/214/262/396 and Thr 231, alleviated the phosphorylation of MAPKs (JNK, ERK1/2, P38), and increased p-GSK-3β (Ser9), while decreased activation of microglia (Iba-1) and astrocytes (GFAP). Moreover, knockdown of MKP-1 in N2A/APP cells inhibited the regulatory effect of SDG on APP, ERK1/2 and JNK.ConclusionsSDG ameliorates Alzheimer-like lesions may be related with increasing MKP-1.