[Frontiers in Bioscience 13, 3470-3479, May 1, 2008]

Involvement of cystatin C in pathophysiology of CNS diseases

Atsushi Nagai1, Masaharu Terashima2, Abdullah Md Sheikh1, Yoshitomo Notsu1, Koichi Shimode3, Shuhei Yamaguchi3, Shotai Kobayashi4, Seung U. Kim5, Junichi Masuda1

1Department of Laboratory Medicine, Shimane University Faculty of Medicine, Izumo, Japan 2Department of Biochemistry and Molecular Medicine, Shimane University Faculty of Medicine, Izumo, Japan 3Department of Internal Medicine III, Shimane University Faculty of Medicine, Izumo, Japan 4University Hospital, Shimane University Faculty of Medicine, Izumo, Japan, 5Division of Neurology, UBC Hospital, University of British Columbia, Vancouver, Canada

TABLE OF CONTENTS

1.Abstract
2. Cystatin C-type cerebral amyloid angiopathy
3. Amyloid fibril formation by cystatin C
4. Concentration in CSF
5. Involvement in AD
6. Involvement in neuronal cell death
7. Conclusions
8. Acknowledgments
9. References

1. ABSTRACT

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.