Aβ25–35 induction of necroptosis through activation of the RIPK1/RIPK3 and RIPK1/ERK1/2 signaling pathways is attenuated with DHA treatment in THP-1 monocytes

Abstract Background: Monocytes play a crucial role in Alzheimer's disease (AD), and docosahexaenoic acid (DHA) treatment has a neuroprotective effect for many neurodegenerative diseases. However, mechanisms that regulate monocyte and Aβ protein interaction in AD and the effects of DHA on monocytes in the context of AD are not fully understood. Methods: The experiments were designed to further explore possible mechanisms of interaction between monocytes and Aβ plaques. Another objective of this study was to investigate a potential mechanism for Aβ-mediated regulation of necroptosis and the MAPK and NF-kB signaling pathways, as well as how these pathways might be modulated by DHA in human THP-1 monocytes. We also investigated whether DHA indirectly suppressed THP-1 cell-mediated neuronal activation. We used cell viability and cytotoxicity assays, flow cytometry, transwell migration assays, and Western blotting to perform our study. Results: Our findings indicate that Aβ25-35 regulates two aspects of THP-1 cells necroptosis. We also observed that increased resistance to apoptosis in THP-1 cells that is correlated with THP-1 monocyte differentiation. Our results also indicated that DHA treatment restored migration of THP-1 monocytes that had been treated with Aβ25–35. Pre-treatment of THP-1 monocytes with DHA effectively inhibited Aβ-induced activation and markedly suppressed protein expression of TNF-α，IL-1β and IL-6. We also found that THP-1 cell necroptosis was induced by Aβ25–35 through modulation of RIPK1/RIPK3 and phosphorylation status of ERK1/2 and could be attenuated by DHA treatment. Conclusion: Aβ25–35-mediated induction of necroptosis through activation of the RIPK1/RIPK3 and RIPK1/ ERK1/2 signaling pathways in THP-1 monocytes can be attenuated by DHA treatment, indicating that DHA treatment could be a promising new therapy for AD management.