Soluble α-synuclein–antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia

Significance Release of oligomeric/fibrillar α-synuclein (αSyn) from damaged neurons contributes to neuronal cell death in Parkinson’s disease and other neurodegenerative disorders in part via microglial activation. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving TLR2 engagement and mitochondrial damage. Oligomerized amyloid-β peptide (Aβ), as found in Alzheimer’s disease brains, exacerbates this neuroinflammation. Importantly, we found that misfolded proteins such as αSyn and Aβ, when bound to antibody and presented to hiMG, result in enhanced proinflammatory response of the NLRP3 inflammasome. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger neuroinflammation in human microglia.