The general mechanisms involved in amyloid formation. The amyloidogenic protein can be synthesized in excess and persist in serum at high concentrations, as for monoclonal light chains or the acute-phase protein serum amyloid A (SAA), or can reach high serum concentrations because of reduced clearance, such as β2-microglobulin in chronic hemodialysis, or can be mutated as in hereditary amyloidosis. Certain proteins with intrinsic amyloidogenic properties, such as transthyretin, can cause amyloidosis late in life, as in senile systemic amyloidosis. Some of these proteins undergo a proteolytic remodeling that facilitates polymerization. The early protein aggregates can exert a direct cytotoxic effect. However, the role of early aggregates/oligomers has not yet been defined in all types of amyloidosis. The concurrence of tissue components and common constituents, such as glycosaminoglycans (GAGs) and serum amyloid P (SAP) component favors formation and persistence of tissue deposits of amyloid fibrils which contribute to causing the dysfunction of the target organ. Illustration by Marie Dauenheimer, adapted from Stone.5
