Human cystatin C expression and regulation by TGF-β1: Implications for the pathogenesis of hereditary cystatin C amyloid angiopathy causing brain hemorrhage

Cystatin C amyloid (ACys) deposition in arteries of the brain is the primary cause of cerebral hemorrhage in hereditary cystatin C amyloid angiopathy (HCCAA). A missense mutation (codon 68; Leu 68 → Gln 68) in the human cystatin C gene renders cystatin C amyloidogenic and in addition leads to a significant reduction in the concentration of cystatin C in the cerebrospinal fluid. We show that the mutation does not affect the accumulation of cystatin C mRNA in monocytes of affected individuals. Further studies on tissue and cellular distribution of cystatin C mRNA reveal an ubiquitous expression of the molecule. However, these levels vary as much as 13 fold between different tissues, with highest expression levels in pancreas, testis and brain. Results are then presented showing that monocytes exposed to transforming growth factor beta 1 (TGF-β1) exhibit a several fold increase in the expression of cystatin C mRNA and cystatin Cprotein. Here, TGF-β1 stimulates secretion of cystatin C from normal monocytes whilst, in contrast, secretion of cystatin C from Leu 68/Gln 68 monocytes is markedly impaired. It is suggested that TGF-β1 is an effector molecule in acute and local phase regulation of cystatin C to prevent damage of cells and matrix by cysteine proteases. We postulate that synergism between ACys and deficiency of cystatin C, in the amyloid-involved areas, contributes to a more aggressive form of vascular damage and consequently earlier onset of cerebral hemorrhage.