Neuronal cell death induced by cystatin C in vivo and in cultured human CNS neurons is inhibited with cathepsin B.
Cystatin C, a cysteine protease inhibitor, is implicated in pathogenesis of late-onset Alzheimer's disease and other neurological disorders. Our recent study showed that cystatin C injection into rat hippocampus induced neuronal cell death in granule cell layer of dentate gyrus in vivo. We further confirmed that cystatin C neurotoxicity was inhibited by simultaneous coapplication of cathepsin B, a cysteine protease. In vitro cytotoxicity was also studied in cultures of human CNS neurons, mixed cultures with astrocytes and A1 human hybrid neurons. Cystatin C induced neuronal cell death in a dose-dependent manner, which accompanied increased number of TUNEL (+) cells, up-regulation of active caspase-3 and DNA ladder. The results of the present study indicate that cystatin C participates in the process of apoptotic neuronal cell death in experimental conditions by means of inhibitory activity of cysteine proteases, and that cystatin C might be involved in the pathogenesis in human neurological disorders including Alzheimer's disease.
Nagai
Atsushi
A
Department of Neurology, University of British Columbia, Vancouver, Canada. anagai@med.shimane-u.ac.jp
Ryu
Jae K
JK
Terashima
Masaharu
M
Tanigawa
Yoshinori
Y
Wakabayashi
Kiryo
K
McLarnon
James G
JG
Kobayashi
Shotai
S
Masuda
Junichi
J
Kim
Seung U
SU
D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002401:Cathepsin B / Q000494:pharmacology*; D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology* / Q000187:drug effects; D055316:Cystatin C; D015891:Cystatins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D006624:Hippocampus; D006801:Humans; D006822:Hybrid Cells; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008845:Microinjections; D009474:Neurons / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013778:Tetrazolium Salts; D013844:Thiazoles
C525030:CST3 protein, human; C525032:Cst3 protein, rat; D055316:Cystatin C; D015891:Cystatins; D013778:Tetrazolium Salts; D013844:Thiazoles; D004247:DNA; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002401:Cathepsin B; C022616:thiazolyl blue