Brain Trauma Induces Massive Hippocampal Neuron Death Linked to a Surge in β-Amyloid Levels in Mice Overexpressing Mutant Amyloid Precursor Protein |
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| Authors: | Douglas H Smith Michio Nakamura Tracy K McIntosh Jun Wang Amarís Rodríguez Xiao-Han Chen Ramesh Raghupathi Kathryn E Saatman James Clemens M Luise Schmidt Virginia M-Y Lee and John Q Trojanowski |
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| Affiliation: | Douglas H. Smith, Michio Nakamura, Tracy K. McIntosh, Jun Wang, Amarís Rodríguez, Xiao-Han Chen, Ramesh Raghupathi, Kathryn E. Saatman, James Clemens, M. Luise Schmidt, Virginia M-Y Lee, and John Q. Trojanowski |
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| 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 β-amyloid (Aβ) 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 Aβ plaque formation, and evaluated changes in posttraumatic memory function, histopathology, and regional tissue levels of the Aβ peptides Aβ1–40 and Aβ1–42. 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 Aβ 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 Aβ1–40 and sevenfold increase in Aβ1–42 levels selectively in the hippocampus (P < 0.01). These data suggest a mechanistic link between brain trauma and Aβ levels and the death of neurons. |
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