Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome

Hum Mol Genet. 2006 Sep 15;15(18):2752-62. doi: 10.1093/hmg/ddl211. Epub 2006 Aug 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Astrocytes / metabolism
  • Brain / metabolism
  • Brain / pathology
  • Cells, Cultured
  • Disease Models, Animal
  • Down Syndrome / complications
  • Down Syndrome / genetics*
  • Down Syndrome / metabolism*
  • Down Syndrome / pathology
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Hippocampus / metabolism
  • Humans
  • Intellectual Disability / etiology
  • Intellectual Disability / genetics
  • Intellectual Disability / metabolism
  • MAP Kinase Signaling System
  • Male
  • Membrane Potentials
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / metabolism*
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism
  • Neurofibrillary Tangles / pathology
  • Oxidative Stress
  • Phosphorylation
  • Trisomy
  • tau Proteins / chemistry
  • tau Proteins / metabolism*

Substances

  • Amyloid beta-Protein Precursor
  • tau Proteins
  • Adenosine Triphosphate
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3