Traumatic brain injury in young, amyloid-beta peptide overexpressing transgenic mice induces marked ipsilateral hippocampal atrophy and diminished A beta deposition during aging

Traumatic brain injury (TBI) is an epigenetic risk factor for Alzheimer's d isease (AD). To test the hypothesis that TBI contributes to the onset andio r progression of AD-like beta-amyloid peptide (AP) deposits, we studied the long-term effects of TBI in transgenic mice that overexpress human A beta from a mutant A beta precursor protein (APP) minigene driven by a platelet derived (PD) growth factor promoter (PDAPP mice). TBI was induced in 4-mont h-old PDAPP and wild type (WT) mice by controlled cortical impact (CCI). Be cause A beta begins to deposit progressively in the PDAPP brain by 6 months , we examined WT and PDAPP mice at 2, 5, and 8 months after TBI or sham tre atment (i.e., at 6, 9, and 12 months of age). Hippocampal atrophy in the PD APP mice was more severe ipsilateral versus contralateral to TBI, and immun ohistochemical studies with antibodies to different A beta peptides demonst rated a statistically significant reduction in hippocampus and cingulate co rtex A beta deposits ipsilateral versus contralateral to CCI in 9-12 month- old PDAPP mice. Hippocampal atrophy and reduced Ap deposits were not seen i n hippocampus or cingulate cortex of sham-injured PDAPP mice or in any WT m ice. These data suggest that the vulnerability of brain cells to A beta tox icity increases and that the accumulation of AP deposits decrease in the pe numbra of CCI months after TBI. Thus, in addition to providing unique oppor tunities for elucidating genetic mechanisms of AD, transgenic mice that rec apitulate AD pathology also may be relevant animal models for investigating the poorly understood role that TBI and other epigenetic risk factors play in the onset and/or progression of AD. (C) 1999 Wiley-Liss. Inc.