Soluble Alpha-Synuclein-Antibody Complexes Activate The Nlrp3 Inflammasome In Hipsc-Derived Microglia

Parkinson's disease is characterized by accumulation of alpha-synuclein (alpha Syn). Release of oligomeric/fibrillar alpha Syn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar alpha Syn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-alpha Syn antibodies could prevent this effect. Here, we show that alpha Syn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) alpha Syn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, alpha Syn-antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1 beta (IL-1 beta) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-beta peptide (A beta) and its cognate antibody. In vivo, engraftment of hiMG with alpha Syn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by alpha Syn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia.