title: Endogenous aggregates of amyloidogenic cystatin C variant are removed by THP-1 cells in vitro and induce differentiation and a proinflammatory response.
abstract: 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.
authors.affiliation: Departments of Anatomy and Pharmacy, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Jonsdottir
authors.forename: Indiana Elin
authors.initials: IE
authors.lastname: Ingolfsdottir
authors.forename: Finnbogi R
authors.initials: FR
authors.lastname: Thormodsson
authors.forename: Petur Henry
authors.initials: PH
authors.lastname: Petersen
mesh_terms: D002448:Cell Adhesion; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D016657:Cerebral Amyloid Angiopathy; D055316:Cystatin C / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007948:Leukemia, Monocytic, Acute / Q000276:immunology*
chemical_list: D055316:Cystatin C