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

• Published in: Neurobiology of aging Vol. 34; no. 5; pp. 1389 - 1396
• Main Authors: Jonsdottir, Gudrun, Ingolfsdottir, Indiana Elin, Thormodsson, Finnbogi R, Petersen, Petur Henry
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2013
• Subjects: Aging; Alzheimer's disease; Amyloid; Cell Adhesion; Cell Differentiation - drug effects; Cell Line, Tumor; Cerebral Amyloid Angiopathy; Cystatin C; Cystatin C - genetics; Cystatin C - immunology; Cystatin C - pharmacology; Endocytosis - drug effects; Endocytosis - immunology; Genetic Variation - genetics; Humans; Inflammation - immunology; Internal Medicine; Leukemia, Monocytic, Acute - immunology; Neurology; THP-1; THP-1; Cerebral Amyloid Angiopathy; Amyloid; Alzheimer's disease; Cystatin C
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2012.11.012

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.