ABSTRACT
Neuroinflammation is the complex innate immune response of neural tissue to control infection, and Toll-like receptors (TLRs), a major family of pattern recognition receptors (PRRs), have a key role in Alzheimer's disease (AD) progression. Innate immune cells, including macrophages, govern tailored inflammatory gene expression to regulate inflammatory responses, however the role of macrophages in AD pathogenesis is not clear. All TLRs, with the exception of TLR3, recruit the MyD88 adaptor, and evidence indicates a role for this adaptor in inflammatory and cognitive changes in mouse AD models, in addition to amyloid-beta (Aß)-induced inflammatory signalling at a cellular level. In the present study, we employed the use of Aß to induce inflammatory signalling in immortalized macrophages. Data presented herein demonstrate that Aß promoted the nuclear sequestration of NF-κB, and polarized macrophages to an M1 phenotype with downstream consequences on pro-inflammatory cytokine expression. Importantly, Aß-induced TNF-α production was exacerbated in macrophages lacking MyD88, while MyD88 deficiency promoted NF-κB activation, enhanced M1 and M2 polarization, and compromised macrophage viability. We demonstrate that in the absence of MyD88, mitogen-activated protein kinase (MAPKs) act as upstream signalling intermediates targeted by Aß in the cascade leading to TNF-α expression. Our findings offer a new role for MyD88 in cellular mechanisms underlying AD pathogenesis, indicating that MyD88 adaptors are key in regulating Aß-induced inflammatory signalling in macrophages.
