title: Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome.
abstract: 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-beta 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 GSK3beta and JNK/SAPK activities and unaltered AbetaPP 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.
authors.affiliation: Laboratory for Neurogenetics, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: Ebrahim Abdul
authors.initials: EA
authors.lastname: Shukkur
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shimohata
authors.forename: Takumi
authors.initials: T
authors.lastname: Akagi
authors.forename: Wenxin
authors.initials: W
authors.lastname: Yu
authors.forename: Mika
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Miyuki
authors.initials: M
authors.lastname: Murayama
authors.forename: Dehua
authors.initials: D
authors.lastname: Chui
authors.forename: Tamaki
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Amano
authors.forename: Karthik Harve
authors.initials: KH
authors.lastname: Subramhanya
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hashikawa
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sago
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Epstein
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takashima
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamakawa
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000150:complications / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000473:pathology; D018384:Oxidative Stress; D010766:Phosphorylation; D014314:Trisomy; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; D000255:Adenosine Triphosphate; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3