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(American Journal of Pathology. 1998;153:1005-1010.)
© 1998 American Society for Investigative Pathology

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Brain Trauma Induces Massive Hippocampal Neuron Death Linked to a Surge in ß-Amyloid Levels in Mice Overexpressing Mutant Amyloid Precursor Protein

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

From the Department of Neurosurgery * and the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and the Lilly Research Labortories, Lilly Corporate Center, Indianapolis, Indiana

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 ß-amyloid (Aß) 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 Aß plaque formation, and evaluated changes in posttraumatic memory function, histopathology, and regional tissue levels of the Aß peptides Aß_1–40 and Aß_1–42. 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 Aß 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 Aß_1–40 and sevenfold increase in Aß_1–42 levels selectively in the hippocampus (P < 0.01). These data suggest a mechanistic link between brain trauma and Aß levels and the death of neurons.

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