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The Journal of Neuroscience, October 1, 2001, 21(19):7526-7533
Involvement of Nitric Oxide Released from Microglia-Macrophages
in Pathological Changes of Cathepsin D-Deficient Mice
Hiroshi
Nakanishi1,
Jian
Zhang2,
Masato
Koike3,
Tsuyoshi
Nishioku2,
Yoshiko
Okamoto4,
Eiki
Kominami5,
Kurt
von
Figura6,
Christoph
Peters7,
Kenji
Yamamoto2,
Paul
Saftig6, and
Yasuo
Uchiyama3
Laboratory of 1 Oral Aging Science and
2 Biochemical and Molecular Pharmacology, Division of Oral
Biological Sciences, Faculty of Dental Sciences, Kyushu University,
Fukuoka 812-8582, Japan, 3 Department of Cell Biology and
Neuroscience, Osaka University Graduate School of Medicine,
Suita, Osaka 565-0871, Japan, 4 Department of
Physiological Chemistry, Daiichi Pharmaceutical University, Fukuoka
815-8511, Japan, 5 Department of Biochemistry, Juntendo
University School of Medicine, Tokyo 113-0033, Japan,
6 Center for Biochemistry and Molecular Cell Biology,
Göttingen University, Heinrich-Düker Weg 12, 37073 Göttingen, Germany, and 7 Institut für
Molekulare Medizin und Zellforschung, Albert-Ludwings-Universität
Freiburg Hugstetter Strasse 55, 79106 Freiburg, Germany
Cathepsin D (CD) deficiency has been shown to induce
ceroid-lipofuscin storage in lysosomes of mouse CNS neuron (Koike et al., 2000). To understand the behavior of microglial cells
corresponding to these neuronal changes, CD-deficient (CD /) mice,
which die at approximately postnatal day (P) 25 by intestinal necrosis, were examined using morphological as well as biochemical approaches. Light and electron microscopic observations revealed that microglia showing large round cell bodies with few processes appeared in the
cerebral cortex and thalamus after P16. At P24, microglia often
encircled neurons that were occupied with autolysosomes, indicating increased phagocytic activity. These morphologically transformed microglia markedly expressed inducible nitric oxide synthase (iNOS), which was also detected in the intestine of the mice.
To assess the role of microglial nitric oxide (NO) in neuropathological changes in CD/ mice,
L-NG-nitro-arginine
methylester (L-NAME), a competitive NOS inhibitor, or S-methylisothiourea hemisulfate (SMT), an iNOS inhibitor, was administered intraperitoneally for 13 consecutive days. The total number of terminal deoxynucleotidyl transferase-mediated
biotinylated UTP nick end labeling-positive cells counted in the
thalamus was found to be significantly decreased by chronic treatment
of L-NAME or SMT, whereas neither the neuronal accumulation
of ceroid-lipofuscin nor the microglial phagocytic activity was
affected by these treatments. Moreover, the chronic treatment of
L-NAME or SMT completely suppressed hemorrhage-necrotic
changes in the small intestine of CD/ mice, resulting in normal
growth of the body weight of the mice. These results suggest that NO
production via iNOS activity in microglia and peripheral macrophages
contributes to secondary tissue damages such as neuronal apoptosis and
intestinal necrosis, respectively.
Key words:
cathepsin D-deficient mouse; microglia; nitric oxide; L-NG-nitro-arginine
methylester; apoptotic neuron; intestinal atrophy
Copyright © 2001 Society for Neuroscience 0270-6474/01/21197526-08$05.00/0
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