title: Strong Correlation of Genome-Wide Expression after Traumatic Brain Injury In Vitro and In Vivo Implicates a Role for SORLA.
abstract: The utility of in vitro models of traumatic brain injury (TBI) depends on their ability to recapitulate the in vivo TBI cascade. In this study, we used a genome-wide approach to compare changes in gene expression at several time points post-injury in both an in vitro model and an in vivo model of TBI. We found a total of 2073 differentially expressed genes in our in vitro model and 877 differentially expressed genes in our in vivo model when compared to noninjured controls. We found a strong correlation in gene expression changes between the two models (r = 0.69), providing confidence that the in vitro model represented at least part of the in vivo injury cascade. From these data, we searched for genes with significant changes in expression over time (analysis of covariance) and identified sorting protein-related receptor with A-type repeats (SORLA). SORLA directs amyloid precursor protein to the recycling pathway by direct binding and away from amyloid-beta producing enzymes. Mutations of SORLA have been linked to Alzheimer's disease (AD). We confirmed downregulation of SORLA expression in organotypic hippocampal slice cultures by immunohistochemistry and Western blotting and present preliminary data from human tissue that is consistent with these experimental results. Together, these data suggest that the in vitro model of TBI used in this study strongly recapitulates the in vivo TBI pathobiology and is well suited for future mechanistic or therapeutic studies. The data also suggest the possible involvement of SORLA in the post-traumatic cascade linking TBI to AD.
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University , New York, New York.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lamprecht
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University , New York, New York.|2 MEA Forensic Engineers & Scientists , Mississauga, Ontario, Canada .
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Elkin
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University , New York, New York.
authors.forename: Kartik
authors.initials: K
authors.lastname: Kesavabhotla
authors.affiliation: 3 Department of Pathology, Fishberg Department of Neuroscience, Friedman Brain Institute , and the Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: John F
authors.initials: JF
authors.lastname: Crary
authors.affiliation: 4 Office of Chief Medical Examiner , City of New York, New York, New York.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hammers
authors.affiliation: 5 Department of Anesthesia and Critical Care, Children's Hospital of Philadelphia , Philadelphia, Pennsylvania.
authors.forename: Jimmy W
authors.initials: JW
authors.lastname: Huh
authors.affiliation: 6 Department of Neurobiology and Anatomy, Drexel University College of Medicine , Philadelphia, Pennsylvania.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Raghupathi
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University , New York, New York.
authors.forename: Barclay
authors.initials: B
authors.lastname: Morrison
mesh_terms: D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D000070642:Brain Injuries, Traumatic / Q000235:genetics* / Q000473:pathology*; D002478:Cells, Cultured; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D040081:Protein Array Analysis / Q000379:methods; D017207:Rats, Sprague-Dawley; D055815:Young Adult
chemical_list: D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; C102582:SORL1 protein, human
keywords: genomics; in vitro studies; in vivo studies; traumatic brain injury