Poster Presentations

Session Title: Apolipoprotein-E
Presentation Date: Thursday, March 12 – Friday, March 13 ,2009

LACK OF GENOTYPIC DIFFERENCES IN BRAIN PATHOLOGY IN HUMAN APOE-TARGETED-REPLACEMENT MICE

S.B. Shelton, K.A. Crutcher
University of Cincinnati, Neurosurgery, Cincinnati, United States

The APOE-ε4 allele is strongly associated with the risk of Alzheimer's disease and worsened outcome after traumatic brain injury (TBI). Proteolytic fragments of apoE have been suggested to play a role in neuronal degeneration and have been observed in Alzheimer's disease brain. To investigate the role of apoE, we studied human APOE-targeted-replacement mice expressing each of the human APOE alleles (ε2,ε3,ε4). We evaluated the APOE genotype response to TBI (controlled cortical impact). No genotypic differences in functional recovery, lesion cavity volume, GFAP immunoreactivity, neuronal loss, or brain apoE levels were found. Furthermore, no apoE fragments were observed. We evaluated conditions of proteolysis of human apoE in mouse brain in vitro. Incubation of APOE-targeted-replacement mouse brain tissue resulted in proteolysis of all 3 isoforms. Of a panel of 12 different protease inhibitors, proteolysis was inhibited only in the presence of the aspartic protease inhibitor pepstatin A. No genotypic differences in the rate of proteolysis were observed either in the presence or absence of pepstatin A. As in human brain tissue, the results are consistent with a role for cathepsin D or similar protease in the degradation of apoE. The lack of genotypic effects may be the result of differences in protein interactions, expression, and/or regulation of apoE in the mouse vs. the human brain. Whatever the reason, the targeted-replacement mouse model for APOE genotype, does not provide clear parallels with human neuropathology but may provide a means to study the proteolytic fate of this protein.