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

Traumatic brain injury (TBI) is an epigenetic risk factor for Alzheimer's disease (AD). To test the hypothesis that TBI contributes to the onset and/or progression of AD-like beta-amyloid peptide (Abeta) deposits, we studied the long-term effects of TBI in transgenic mice that overexpress human Abeta from a mutant Abeta precursor protein (APP) minigene driven by a platelet derived (PD) growth factor promoter (PDAPP mice). TBI was induced in 4-month-old PDAPP and wild type (WT) mice by controlled cortical impact (CCI). Because Abeta 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 treatment (i.e., at 6, 9, and 12 months of age). Hippocampal atrophy in the PDAPP mice was more severe ipsilateral versus contralateral to TBI, and immunohistochemical studies with antibodies to different Abeta peptides demonstrated a statistically significant reduction in hippocampus and cingulate cortex Abeta deposits ipsilateral versus contralateral to CCI in 9-12 month-old PDAPP mice. Hippocampal atrophy and reduced Abeta deposits were not seen in hippocampus or cingulate cortex of sham-injured PDAPP mice or in any WT mice. These data suggest that the vulnerability of brain cells to Abeta toxicity increases and that the accumulation of Abeta deposits decrease in the penumbra of CCI months after TBI. Thus, in addition to providing unique opportunities for elucidating genetic mechanisms of AD, transgenic mice that recapitulate 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.

Nakagawa Y ，Nakamura M ，McIntosh TK ，Rodriguez A ，Berlin JA ，Smith DH ，Saatman KE ，Raghupathi R ，Clemens J ，Saido TC ，Schmidt ML ，Lee VM ，Trojanowski JQ ... -  《JOURNAL OF COMPARATIVE NEUROLOGY》

Brain trauma in aged transgenic mice induces regression of established abeta deposits.

Traumatic brain injury (TBI) increases susceptibility to Alzheimer's disease (AD), but it is not known if TBI affects the progression of AD. To address this question, we studied the neuropathological consequences of TBI in transgenic (TG) mice with a mutant human Abeta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter resulting in overexpression of mutant APP (V717F), elevated brain Abeta levels, and AD-like amyloidosis. Since brain Abeta deposits first appear in 6-month-old TG (PDAPP) mice and accumulate with age, 2-year-old PDAPP and wild-type (WT) mice were subjected to controlled cortical impact (CCI) TBI or sham treatment. At 1, 9, and 16 weeks after TBI, neuron loss, gliosis, and atrophy were most prominent near the CCI site in PDAPP and WT mice. However, there also was a remarkable regression in the Abeta amyloid plaque burden in the hippocampus ipsilateral to TBI compared to the contralateral hippocampus of the PDAPP mice by 16 weeks postinjury. Thus, these data suggest that previously accumulated Abeta plaques resulting from progressive amyloidosis in the AD brain also may be reversible.

Nakagawa Y ，Reed L ，Nakamura M ，McIntosh TK ，Smith DH ，Saatman KE ，Raghupathi R ，Clemens J ，Saido TC ，Lee VM ，Trojanowski JQ ... -  《EXPERIMENTAL NEUROLOGY》

Genomic analysis of response to traumatic brain injury in a mouse model of Alzheimer's disease (APPsw).

Crawford FC ，Wood M ，Ferguson S ，Mathura VS ，Faza B ，Wilson S ，Fan T ，O'Steen B ，Ait-Ghezala G ，Hayes R ，Mullan MJ ... -  《BRAIN RESEARCH》

Caspase inhibition therapy abolishes brain trauma-induced increases in Abeta peptide: implications for clinical outcome.

Abrahamson EE ，Ikonomovic MD ，Ciallella JR ，Hope CE ，Paljug WR ，Isanski BA ，Flood DG ，Clark RS ，DeKosky ST ... -  《EXPERIMENTAL NEUROLOGY》

Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice.

Malm TM ，Koistinaho M ，Pärepalo M ，Vatanen T ，Ooka A ，Karlsson S ，Koistinaho J ... -  《NEUROBIOLOGY OF DISEASE》