Human Molecular Genetics Advance Access originally published online on August 4, 2006
Human Molecular Genetics 2006 15(18):2752-2762; doi:10.1093/hmg/ddl211
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Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome
1 Laboratory for Neurogenetics, 2 Laboratory for Alzheimer's Disease and 3 Laboratory for Neural Architecture, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan, 4 Division of Fetal Medicine, National Center for Child Health & Development, Tokyo, Japan and 5 Department of Pediatrics, University of California, San Francisco, CA, USA
* To whom correspondence should be addressed at: Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan. Tel: +81 48 467 9703; Fax: +81 48 467 7095; Email: yamakawa{at}brain.riken.jp
Received May 30, 2006; Accepted August 1, 2006
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-ß 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 GSK3ß and JNK/SAPK activities and unaltered AßPP 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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