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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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 Aβ(1-40) and Aβ(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 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 Aβ(1-40) and sevenfold increase in Aβ(1-42) 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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Smith, D. H., Nakamura, M., McIntosh, T. K., Wang, J., Rodríguez, A., Chen, X. H., … Trojanowski, J. Q. (1998). Brain trauma induces massive hippocampal neuron death linked to a surge in β-amyloid levels in mice overexpressing mutant amyloid precursor protein. American Journal of Pathology, 153(3), 1005–1010. https://doi.org/10.1016/S0002-9440(10)65643-X

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