title: Brain trauma induces massive hippocampal neuron death linked to a surge in beta-amyloid levels in mice overexpressing mutant amyloid precursor protein.
abstract: 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.
authors.affiliation: Department of Neurosurgery, University of Pennsylvania, Philadelphia 19104-6316, USA. smithdou@mail.med.upenn.edu
authors.forename: D H
authors.initials: DH
authors.lastname: Smith
authors.forename: M
authors.initials: M
authors.lastname: Nakamura
authors.forename: T K
authors.initials: TK
authors.lastname: McIntosh
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez
authors.forename: X H
authors.initials: XH
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Raghupathi
authors.forename: K E
authors.initials: KE
authors.lastname: Saatman
authors.forename: J
authors.initials: J
authors.lastname: Clemens
authors.forename: M L
authors.initials: ML
authors.lastname: Schmidt
authors.forename: V M
authors.initials: VM
authors.lastname: Lee
authors.forename: J Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016923:Cell Death; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010052:Ovariectomy
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor