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J. Biol. Chem., Vol. 280, Issue 29, 27296-27302, July 22, 2005

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Neurodegeneration in Heterozygous Niemann-Pick Type C1 (NPC1) Mouse

IMPLICATION OF HETEROZYGOUS NPC1 MUTATIONS BEING A RISK FOR TAUOPATHY^*

Wenxin Yu, Mihee Ko, Katsuhiko Yanagisawa, and Makoto Michikawa

From the Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan

Niemann-Pick type C1 (NPC1) disease is an autosomal recessive, fatal disorder characterized by a defect in cholesterol trafficking and progressive neurodegeneration. The disease is predominantly caused by mutations in the NPC1 gene; however, it has been assumed that heterozygous NPC1 mutations do not cause any symptoms. Here we demonstrate that cholesterol accumulation does not occur in young mouse brains; however, it does in aged (104-106-week-old) NPC1+/- mouse brains. In addition, Purkinje cell loss was observed in aged NPC1+/- mouse cerebellums. Immunoblot analysis using anti-phospho-tau antibodies (AT-8, AT-100, AT-180, AT-270, PHF-1, and SMI-31) demonstrates the site-specific phosphorylation of tau at Ser-199, Ser-202, Ser-212, and Thr-214 in the brains of aged NPC1+/- mice. Mitogen-activated protein kinase, a potential serine kinase known to phosphorylate tau, was activated, whereas other serine kinases, including glycogen synthase kinase 3, cyclin-dependent kinase 5, or stress-activated protein kinase/c-Jun N-terminal kinase were not activated. Cholesterol level in the lipid raft isolated from the cerebral cortices, ATP level, and ATP synthase activity in the cerebral cortices significantly decreased in the aged NPC1+/- brains compared with those in the NPC1+/+ brains. All of these changes observed in NPC1+/- brains were determined to be associated with aging and were not observed in the age-matched NPC1+/+ brains. These results clearly demonstrate that heterozygous NPC1 impairs neuronal functions and causes neurodegeneration in aged mouse brains, suggesting that human heterozygous NPC1 mutations may be a risk factor for neurodegenerative disorders, such as tauopathy, in the aged population.

Received for publication, April 11, 2005 , and in revised form, May 18, 2005.

^* This work was supported by grants from the Ministry of Health, Labor, and Welfare of Japan (Comprehensive Research on Aging and Health Grant H14-10 and Research on Human Genome and Tissue Engineering Grant H17-004), by the Pharmaceuticals and Medical Devices Agency, Japan, and by the National Niemann-Pick Disease Foundation, USA. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 81-562-46-2311; Fax: 81-562-46-3157; E-mail: michi{at}nils.go.jp.

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