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

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.
AuthorsGudrun Jonsdottir, Indiana Elin Ingolfsdottir, Finnbogi R Thormodsson, Petur Henry Petersen
JournalNeurobiology of aging (Neurobiol Aging) Vol. 34 Issue 5 Pg. 1389-96 (May 2013) ISSN: 1558-1497 [Electronic] United States
PMID23273574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Inc. All rights reserved.
Chemical References
  • Cystatin C
  • Cell Adhesion
  • Cell Differentiation (drug effects)
  • Cell Line, Tumor
  • Cerebral Amyloid Angiopathy
  • Cystatin C (genetics, immunology, pharmacology)
  • Endocytosis (drug effects, immunology)
  • Genetic Variation (genetics)
  • Humans
  • Inflammation (immunology)
  • Leukemia, Monocytic, Acute (immunology)

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