Polymorphic SERPINA3-R124C reduces pathogenesis of its wild type by shortening the lifetime of oligomeric Aβ

Amyloid beta (Aβ) 42 peptide accumulated in Alzheimer disease (AD) patients’ brain, often colocalized with serine protease inhibitor family A member 3 (SERPINA3). Being a chaperon, SERPINA3 accelerated Aβ42 fibrillization. While analyzing chaperon activity of human SERPINA3 polymorphisms, we found SERPINA3-R124C played a role in protecting cells from Aβ42 cytotoxicity. SH-SY5Y cells exposed to Aβ42 preincubated with wild-type SERPINA3 (SERPINA3-WT) resulted in extended toxicity leading cell death whereas Aβ42 with SERPINA3-R124C resulted in less cytotoxicity. Transmission electron microscope and thioflavin T assay revealed that SERPINA3-R124C shortened lifetime of small soluble oligomer and maintained β-sheet rich protofibril-like aggregates for longer time compared to that of with SERPINA3-WT. Western blot assay confirmed that SERPINA3-R124C converted Aβ42 mostly into high molecular aggregates. Here, we demonstrate first time that polymorphic SERPINA3 acts as a benign chaperon by modulating the transition states of Aβ42, which may contribute to the reduction of AD risk.Graphical AbstractSketch of benign chaperon activity of polymorphic SERPINA3-R124C. Here, A = Absence of any SERPINA3 (Aβ42 alone); B = Aβ42 + SERPINA3-WT (WT sample); C = Aβ42 + SERPINA3-R124C (R124C sample).