Brain trauma induces massive hippocampal neuron death linked to a surge in beta-amyloid levels in mice overexpressing mutant amyloid precursor protein

Am J Pathol. 1998 Sep;153(3):1005-10. doi: 10.1016/s0002-9440(10)65643-x.


Although brain trauma is a risk factor for Alzheimer's disease, no experimental model has been generated to explore this relationship. We developed a model of brain trauma in transgenic mice that overexpress mutant human amyloid precursor protein (PDAPP) leading to the appearance of Alzheimer's disease-like beta-amyloid (Abeta) plaques beginning at 6 months of age. We induced cortical impact brain injury in the PDAPP animals and their wild-type littermates at 4 months of age, ie, before Abeta plaque formation, and evaluated changes in posttraumatic memory function, histopathology, and regional tissue levels of the Abeta peptides Abeta1-40 and Abeta1-42. We found that noninjured PDAPP mice had impaired memory function compared to noninjured wild-type littermates (P < 0.01) and that brain-injured PDAPP mice had more profound memory dysfunction than brain-injured wild-type littermates (P < 0.001). Although no augmentation of Abeta plaque formation was observed in brain-injured PDAPP mice, a substantial exacerbation of neuron death was found in the hippocampus (P < 0.001) in association with an acute threefold increase in Abeta1-40 and sevenfold increase in Abeta1-42 levels selectively in the hippocampus (P < 0.01). These data suggest a mechanistic link between brain trauma and Abeta levels and the death of neurons.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Brain Injuries / metabolism
  • Brain Injuries / pathology*
  • Brain Injuries / physiopathology
  • Cell Death
  • Disease Models, Animal
  • Female
  • Hippocampus / metabolism
  • Hippocampus / pathology*
  • Hippocampus / physiopathology
  • Maze Learning
  • Mice
  • Mice, Transgenic
  • Neurons / metabolism
  • Neurons / pathology*
  • Ovariectomy


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor