Soluble Aβ1-42 suppresses TNF-α and activates NLRP3 inflammasome in THP-1 macrophages

Deposition of amyloid-beta in Alzheimer's disease is accompanied by chronic inflammation, which involves raised levels of pro-inflammatory cytokines TNF-alpha, IL-6 and IL-1 beta. However, the role of A beta(1-42) in the inflammatory process, before it gets deposited into aggregates has not been investigated thoroughly. Through this study, we are illustrating the dual role of soluble A beta(1-42) (sA beta(1-42)) in activating the NLRP3 inflammasome and simultaneously inhibiting TNF-alpha secretion. Our data suggested that the treatment of chronically induced THP-1 macrophages and N9 microglial cells with sA beta(1-42) can suppress the major inflammatory cytokine TNF-alpha without affecting the level of IL-6. However, the activation of NLRP3 inflammasome was well evidenced by secretion of IL-1 beta, increased expression of NLRP3 and caspase-1, implicating sA beta(1-42) in enhancing and suppressing one or other type of inflammation. Further investigation revealed that sA beta(1-42) was able to severely abrogate the expression of NF-kappa B, p50 and restricting the translocation of NF-kappa B, p65 to nucleus by inhibiting phosphorylation of I kappa B-alpha in THP-1 macrophages. These data indicate that the sA beta(1-42) may play a dual role during inflammatory process, wherein, it may be involved in protecting the cells from inflammatory damage due to TNF-alpha. This ability of sA beta(1-42) might be playing some role in protecting the brain cells during the process of aging and Alzheimer's disease, where, chronic inflammatory environment plays a vital role.