On the role of monocytes/macrophages in the pathogenesis of central nervous system lesions in hereditary cystatin C amyloid angiopathy.
The pathogenesis of the deposition of a variant cystatin C as amyloid in hereditary cystatin C amyloid angiopathy (HCCAA) is not known. To address this question the synthesis and secretion of cystatin C in cultured monocytes from 9 carriers of the mutated cystatin C gene (5 symptomatic and 4 asymptomatic) was examined. The quantity of cystatin C in cells and supernatants was determined by the ELISA method, Western blots were done and selected samples immunostained for cystatin C. Monocytes from individuals carrying the gene defect synthesized cystatin C that was apparently not truncated, a form found in the cerebral amyloid deposits in HCCAA, but showed a distinctly lower rate of cystatin C synthesis than monocytes from healthy controls. The main difference was that the quantity of cystatin C was significantly lower in the supernatants in monocyte cultures from carriers of the gene defect than from healthy controls, possibly due to a partial block in its secretion. This abnormal processing of the cystatin C could explain the low cerebrospinal fluid levels of cystatin C in HCCAA and might be a part of the pathogenetic pathway of amyloid deposition. Furthermore it could, through a lower extracellular concentration of this inhibitor of cysteine proteinases, contribute to destruction of the amyloidotic blood vessels, leading to the most serious clinical manifestation in HCCAA, intracerebral hemorrhage.
Thorsteinsson
L
L
Department of Medical Genetics, National University Hospital, Reykjavík, Iceland.
Georgsson
G
G
Asgeirsson
B
B
Bjarnadóttir
M
M
Olafsson
I
I
Jensson
O
O
Gudmundsson
G
G
D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002478:Cells, Cultured; D016657:Cerebral Amyloid Angiopathy / Q000097:blood* / Q000235:genetics; D002556:Cerebrospinal Fluid Proteins / Q000235:genetics; D055316:Cystatin C; D015891:Cystatins / Q000097:blood / Q000235:genetics* / Q000302:isolation & purification; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology*
C525030:CST3 protein, human; D002556:Cerebrospinal Fluid Proteins; D055316:Cystatin C; D015891:Cystatins