• Fiona C Crawford, Marcie Wood, Scott Ferguson, Venkatarajan S Mathura, Brandon Faza, Sarah Wilson, Tao Fan, Barbara O'Steen, Ghania Ait-Ghezala, Ronald Hayes, and Michael J Mullan.
• Roskamp Institute, 2040 Whitfield Ave., Sarasota, FL 34243, USA. fcrawford@rfdn.org
• Brain Res. 2007 Dec 14;1185:45-58.

AbstractNumerous studies have shown that the beta-amyloid peptide (Abeta) or beta-amyloid deposits impact many processes that can contribute to neurodegeneration, ranging from immune and inflammatory processes to cell death and apoptosis, processes characteristic of both Alzheimer's disease and head injury. Human and animal studies of traumatic brain injury (TBI) have shown that Abeta production is increased acutely following injury, and there is evidence for increased amyloid deposition and risk for Alzheimer's disease following TBI. Given the poorer outcome after injury observed both in transgenic mice overproducing Abeta, as well as in humans subjected to repetitive head injury, one may conclude that the presence of elevated brain levels of Abeta, whether endogenous or as a consequence of previous injury, exacerbates many of the deleterious processes triggered by TBI. We sought to test this hypothesis by examining the genomic response to injury in wild-type mice and in transgenic mice (APPsw) overexpressing and accumulating cerebral Abeta/beta-amyloid. Gene expression was investigated by microarray 24 h after controlled cortical impact (CCI) injury or sham injury in aged APPsw transgenic mice and wild-type controls. Stringent statistical analysis revealed differential expression of a total of 129 genes in the transgenic TBI vs. sham comparison and 119 genes in the wild-type TBI vs. sham comparison. Of these, only 28 genes were common to both comparisons, suggesting considerable differences in response to injury in the Alzheimer models compared to wild-type mice. We focused our analyses by creating a "genotype-dependent" data set of response to injury which contained the genes that were uniquely altered in response to injury in either wild-type or APPsw mice, as well as those which were significantly differently modulated following TBI in one genotype compared to the other. The cellular functions predicted to be influenced by these changes in gene expression thus indicate the adverse pathways triggered by increased levels of Abeta, and the potentially favorable (recovery) pathways which are activated in wild-type mice but suppressed when Abeta levels are high. The results show that the cellular functions most influenced by the cerebral Abeta levels following TBI include inflammation, immune response, and cell death, which suggest a particular vulnerability to head injury in the Alzheimer brain.

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