Involvement of cystatin C in pathophysiology of CNS diseases.
Cystatin C Leu68Gln variant is known to induce amyloid deposition in cerebral arterioles, resulting in Icelandic type cerebral amyloid angiopathy (CAA). Wild-type cystatin C is also observed in solitary CAA involving amyloid beta protein (Abeta), and accelerates the amyloidogenicity of Abeta in vitro. In neurological inflammatory diseases and leptomeningeal metastasis, low cystatin C levels are accompanied with high activities of cathepsins in the cerebrospinal fluid. Among the cells in CNS, astrocytes appear to secrete cystatin C in response to various proteases and cytokines. Co-localization of Abeta and cystatin C in the brains of Alzheimer's disease (AD) led to the hypothesis that cystatin C is involved in the disease process. We demonstrated that cystatin C microinjection into rat hippocampus induced neuronal cell death in dentate gyrus. Furthermore, apoptotic cell death was observed in neuronal cells treated with cystatin C in vitro. Up-regulation of cystatin C was observed in glial cells with neuronal cell death in vivo. These findings indicate the involvement of cystatin C in the process of neuronal cell death.
Department of Laboratory Medicine, Shimane University Faculty of Medicine, Izumo, Japan. anagai@med.shimane-u.ac.jp
Atsushi
A
Nagai
Masaharu
M
Terashima
Abdullah Md
AM
Sheikh
Yoshitomo
Y
Notsu
Koichi
K
Shimode
Shuhei
S
Yamaguchi
Shotai
S
Kobayashi
Seung U
SU
Kim
Junichi
J
Masuda
D019943:Amino Acid Substitution; D000686:Amyloidosis / Q000235:genetics / Q000473:pathology; D016923:Cell Death; D002493:Central Nervous System Diseases / Q000473:pathology / Q000503:physiopathology*; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000473:pathology; D002556:Cerebrospinal Fluid Proteins / Q000502:physiology; D055316:Cystatin C; D015891:Cystatins / Q000134:cerebrospinal fluid / Q000235:genetics / Q000502:physiology*; D014644:Genetic Variation; D006801:Humans; D007249:Inflammation / Q000517:prevention & control
C525030:CST3 protein, human; D002556:Cerebrospinal Fluid Proteins; C525032:Cst3 protein, rat; D055316:Cystatin C; D015891:Cystatins