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Role of APOE Isoforms in the Pathogenesis of TBI induced Alzheimer's Disease

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University of Pittsburgh Pittsburgh United States

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During the reported period, we completed the behavioral tests with Abca1 deficient mice. Three behavioral paradigms were used to evaluate the differences in cognitive performance between the genotypes and age groups following TBI the analysis of the data generated in the Elevated Plus Maze paradigm demonstrated significant increase in anxiety related behavior with a difference between sham and injured WT or Abca1 deficient mice expressing APOE4. In the MWM paradigm, both Abca1 deficient genotypes had performance significantly affected by training and genotypeinjury, and the analysis suggested a negative effect of Abca1 deficiency in mice expressing either isoform. TBI had no effect on performance of fear conditioning in Abca1 deficient mice regardless of the expressed APOE isoform. Targeted RT-QPCR for genes involved in inflammatory response, demonstrated that the injury affects transcriptional activity beyond the adjacent tissue and likely the entire brain. We continued the analysis of the changes in the transcriptome of young and aged APOE3 and APOE4 mice expressing two copies of Abca1 with the goal to identify co-expression gene networks correlated to the traits age injury genotype in response to TBI. The results clearly demonstrate segregation by injury status and separation by APOE isoform, although not as strong as expected. Most importantly the networks identified by correlation analysis corresponded to GO terms immune response, innate immunity with differential expression of genes involved in pattern recognition and phagocytosis. The results of the study at this stage have been presented at three scientific meetings and a manuscript is being submitted.

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Technical Report,30 Sep 2015,29 Sep 2016



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Approved For Public Release;

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