Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome.
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.
Shukkur
Ebrahim Abdul
EA
Laboratory for Neurogenetics, RIKEN Brain Science Institute, Saitama, Japan.
Shimohata
Atsushi
A
Akagi
Takumi
T
Yu
Wenxin
W
Yamaguchi
Mika
M
Murayama
Miyuki
M
Chui
Dehua
D
Takeuchi
Tamaki
T
Amano
Kenji
K
Subramhanya
Karthik Harve
KH
Hashikawa
Tsutomu
T
Sago
Haruhiko
H
Epstein
Charles J
CJ
Takashima
Akihiko
A
Yamakawa
Kazuhiro
K
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*
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