Endogenous aggregates of amyloidogenic cystatin C variant are removed by THP-1 cells in vitro and induce differentiation and a proinflammatory response.

[hereditary cerebral hemorrhage with amyloidosis]

A mutation in the human cystatin C gene leads to familial cerebral amyloid angiopathy . This disease is known as "hereditary cerebral hemorrhage with amyloidosis -Icelandic type " or "hereditary cystatin C amyloid angiopathy ." The mutant cystatin C protein forms aggregates and amyloid , within the central nervous system almost exclusively in connection with the vascular system . It was not known whether immune cells could remove mutant cystatin C protein aggregates . Ex vivo mutant cystatin C protein aggregates , both in solution and dried onto a glass surface , induced adhesion to the substrate , differentiated the THP-1 monocyte cell line and led to a proinflammatory response . Aggregates were also taken up by both THP-1 cells and THP-1 derived macrophages . These are the same responses induced by other amyloidogenic protein species , such as amyloid β protein and amylin , supporting the model of all amyloidogenic proteins being toxic due to common structural motifs . Proinflammatory response induced by the ex vivo mutant cystatin C protein aggregates suggests that vascular inflammation plays an important role in hereditary cerebral hemorrhage with amyloidosis -Icelandic type . Ex vivo protein aggregates of cystatin C might better model cellular behavior than in vitro-generated aggregates or supplement in vitro material .