Cystatin C colocalizes with amyloid-beta and coimmunoprecipitates with amyloid-beta precursor protein in sporadic inclusion-body myositis muscles.
Cystatin C (CC), an endogenous cysteine protease inhibitor, is accumulated within amyloid-beta (A beta) amyloid deposits in Alzheimer's disease (AD) brain and was proposed to play a role in the AD pathogenesis. Because the chemo-morphologic muscle phenotype of sporadic inclusion-body myositis (s-IBM) has several similarities with the phenotype of AD brain, including abnormal accumulation of A beta deposits, we studied expression and localization of CC in muscle biopsies of 10 s-IBM, and 16 disease- and five normal-control muscle biopsies. Physical interaction of CC with amyloid-beta precursor protein (A beta PP) was studied by a combined immunoprecipitation/immunoblotting technique in the s-IBM muscle biopsies and in A beta PP-overexpressing cultured human muscle fibers. In all s-IBM muscle biopsies, CC-immunoreactivity either colocalized with, or was adjacent to, the A beta-immunoreactive inclusions in 80-90% of the vacuolated muscle fibers, mostly in non-vacuolated regions of their cytoplasm. Ultrastructurally, CC immunoreactivity-colocalized with A beta on 6-10 nm amyloid-like fibrils and floccular material. By immunoblotting, CC expression was strongly increased in IBM muscle as compared to the controls. By immunoprecipitation/immunoblotting experiments, CC coimmunoprecipitated with A beta PP, both in s-IBM muscle and in A beta PP-overexpressing cultured normal human muscle fibers. Our studies (i) demonstrate for the first time that CC physically associates with A beta PP, and (ii) suggest that CC may play a novel role in the s-IBM pathogenesis, possibly by influencing A beta PP processing and A beta deposition.
Vattemi
Gaetano
G
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, California 90017-1912, USA.
Engel
W King
WK
McFerrin
Janis
J
Askanas
Valerie
V
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D001706:Biopsy; D002478:Cells, Cultured; D055316:Cystatin C; D015891:Cystatins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009132:Muscles / Q000378:metabolism* / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D011233:Precipitin Tests
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C525030:CST3 protein, human; D055316:Cystatin C; D015891:Cystatins