DHA attenuates Aß-induced necroptosis through the RIPK1/RIPK3 signaling pathway in THP-1 monocytes.

ABSTRACT

Monocytes play a crucial role in Alzheimer's disease (AD), and docosahexaenoic acid (DHA) has a neuroprotective effect for many neurodegenerative diseases. However, mechanisms that regulate monocyte and Aß protein interaction in AD and the effects of DHA on monocytes in the context of AD are not fully understood. The experiments were designed to further explore possible mechanisms of interaction between monocytes and Aß plaques. Another objective of this study was to investigate a potential mechanism for Aß-induced necroptosis involving the activation of MAPK and NF-kB signaling pathways in human THP-1 monocytes, as well as how these pathways might be modulated by DHA. Our findings indicate that Aß25-35 has a "Hormesis" effect on cell viability and necroptosis in THP-1 cells, and Aß25-35 influences THP-1 cells differentiation as analyzed by flow cytometry. Pretreatment of THP-1 monocytes with DHA effectively inhibited Aß-induced activation and markedly suppressed protein expression of necroptosis (RIPK1, RIPK3, MLKL) and pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6). Moreover, our findings indicate that Aß25-35 activated the ERK1/2 and p38 signaling pathways, but not NF-κB/p65 signaling, while pre-treatment with DHA followed by Aß25-35 treatment suppressed only ERK1/2 signaling. Further study revealed that the expression level of RIPK3 is reduced much more during coadministration with DHA and necrostatin-1 (NEC-1) than administration alone with either of them, indicating that DHA may have additional targets. Meanwhile, this finding indicates that DHA can prevent Aß-induced necroptosis of THP-1 cells via the RIPK1/RIPK3 signaling pathway. Our results also indicate that DHA treatment restored migration of THP-1 monocytes induced by Aß25-35, and DHA treatment could be a promising new therapy for AD management.