Parkinson's disease is characterized by accumulation of alpha-synuclein (alphaSyn). Release of oligomeric/fibrillar alphaSyn from damaged neurons may potentiate neuronal death in part via microglial ...activation. Heretofore, it remained unknown if oligomeric/fibrillar alphaSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflamma-some in human microglia and whether anti-alphaSyn antibodies could prevent this effect. Here, we show that alphaSyn 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) alphaSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, alphaSyn--antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1beta (IL-1beta) secretion, indicating these complexes are neuro-inflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-beta peptide (Abeta) and its cognate antibody. In vivo, engraftment of hiMG with alphaSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by alphaSyn 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. neuroinflammation | Parkinson's disease | Lewy body dementia | Alzheimer's disease | antibody therapies
![Soluble [alpha]-synuclein-a...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0027-8424/small "Soluble [alpha]-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia")