Fig. 4

Proposed scheme for SAA fibril formation. a HDL-bound SAA dissociates from HDL. b {S}AA enters cell via clathrin-coated pits to reside in low pH lysosomal environment. c {S}AA monomers undergo structural rearrangement(s) within lysosome. d AA oligomers form within cells. e Lysis of lysosomal and cellular membranes leads to extracellular oligomers and debris from necrotic cells. f AA oligomers extend into fibrils based on β-pleated sheet domain interactions and become visible as tissue “amyloid” deposits with congo red binding. (modified after Claus et al. (2017), Copyright John Wiley and Sons, 2017, used by permission). As described in the text, cleavage of SAA occurs during this process, generally yielding a 76 aa N-terminal fragment. Cleavage may involve a serine protease on the cell surface (Lavie et al. 1978) but the precise site at which this occurs remains unestablished and the undefined nature of the intracellular species in the early stages (a-c) is indicated by {S}AA. By stage (d) the AA (post-cleavage) species likely predominates