Perturbation of processing of cystatin C in monocytes from patients with hereditary cystatin C amyloid angiopathy

Abstract

In hereditary cystatin C amyloid angiopathy (HCCAA) a mutation of the cystatin C gene occurs with substitution of a single amino acid in the cystatin C protein, which is deposited as amyloid. The pathogenetic mechanism leading to amyloid deposition is unknown. We have in the pursuit of this question studied the processing of cystatin C in blood monocytes from six carriers of the mutated cystatin C gene (three asymptomatic and three had got repeated strokes). Monocytes from blood donors served as controls. The main finding was that monocytes from asymptomatic and symptomatic individuals accumulated cystatin C intracellularly. Thus the concentration of cystatin C was higher in the cells than in the supernatants whereas the opposite was true for the controls. No difference in the intracellular distribution of cystatin C was found by immunohistochemistry and preliminary results of electron microscopic examination have not revealed any distinct difference in the ultrastructure. As microglia are closely related to monocytes, the observed partial block in the secretion of cystatin C in HCCAA may be of relevance for the pathogenesis of the amyloid deposits in the central nervous system (CNS).