BRAIN TRAUMA INDUCES MASSIVE HIPPOCAMPAL NEURON DEATH LINKED TO A SURGE IN BETA-AMYLOID LEVELS IN MICE OVEREXPRESSING MUTANT AMYLOID PRECURSOR PROTEIN

Although brain trauma is a risk factor for Alzheimer's disease, no exp erimental model has been generated to explore this relationship. We de veloped a model of brain trauma in transgenic mice that overexpress mu tant human amyloid precursor protein (PDAPP) leading to the appearance of Alzheimer's disease-like beta-amyloid (A beta) plaques beginning a t 6 months of age. We induced cortical impact brain injury in the PDAP P animals and their wild-type littermates at 4 months of age, ie, befo re A beta plaque formation, and evaluated changes in posttraumatic mem ory function, histopathology, and regional tissue levels of the A beta peptides A beta(1-40) and A beta(1-42). We found that noninjured PDAP P mice had impaired memory function compared to noninjured wild-type l ittermates (P < 0.01) and that brain-injured PDAPP mice had more profo und memory dysfunction than brain-injured wild-type littermates (P < 0 .001), Although no augmentation of A beta plaque formation was observe d in brain-injured PDAPP mice, a substantial exacerbation of neuron de ath was found in the hippocampus (P < 0.001) in association with an ac ute threefold increase in A beta(1-40) and sevenfold increase in A bet a(1-42) levels selectively in the hippocampus (P < 0.01). These data s uggest a mechanistic link between brain trauma and A beta levels and t he death of neurons.