Human Molecular Genetics Advance Access published online on August 4, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl211
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1 Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan
* To whom correspondence should be addressed. Trisomy 21 or Down syndrome (DS) is the most common genetic birth defect associated with mental retardation. The over-expression of genes on chromosome 21, including SOD1 (Cu/Zn superoxide dismutase) and APP (amyloid-
Received May 30, 2006
Revised August 1, 2006
Accepted August 1, 2006
Article
Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome
Ebrahim Abdul Shukkur 1, Atsushi Shimohata 1, Takumi Akagi 2, Wenxin Yu 1, Mika Yamaguchi 1, Miyuki Murayama 3, Dehua Chui 3, Tamaki Takeuchi 1, Kenji Amano 1, Karthik Harve Subramhanya 1, Tsutomu Hashikawa 2, Haruhiko Sago 4, Charles J. Epstein 5, Akihiko Takashima 3, and Kazuhiro Yamakawa 6 *
2 Laboratory for Neural Architecture, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan
3 Laboratory for Alzheimer's Disease, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan
4 Division of Fetal Medicine, National Center for Child Health & Development, Tokyo, Japan
5 Department of Pediatrics, University of California, San Francisco, CA, USA
6 Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan
Kazuhiro Yamakawa, E-mail: yamakawa{at}brain.riken.jp
Abstract 
precursor protein) is believed to underlie the increased oxidative stress and neurodegeneration commonly described in DS. However, a segmental trisomy 16 mouse model for DS, Ts1Cje, has a subset of triplicated human chromosome 21 gene orthologs that exclude APP and SOD1. Here, we report that Ts1Cje brain shows decreases of mitochondrial membrane potential and ATP production, increases of reactive oxygen species, hyperphosphorylation of tau without NFT formation, increase of GSK3 and JNK/SAPK activities, and unaltered APP metabolism. Our findings suggest that genes on the trisomic Ts1Cje segment other than APP and SOD1 can cause oxidative stress, mitochondrial dysfunction, and hyperphosphorylation of tau, all of which may play critical roles in the pathogenesis of mental retardation in DS.
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