Brain and Plasma Molecular Characterization of the Pathogenic TBI-AD Interrelationship in Mouse Models

Traumatic Brain Injury TBI, in particular mild TBI mTBI is a major cause of disability in military and in civilian populations, and for many years has been known to be an epigenetic risk factor for Alzheimers Disease AD and other neurodegenerative conditions such as Parkinsons disease, Amyotrophic Lateral Sclerosis or Chronic Traumatic Encephalopathy CTE Randolph, 2001 Gaetz and Weinberg, 2000 Gaetz et al., 2000 Guskiewicz et al., 2003 Gavett et al., 2011 Van Den Heuvel et al., 2007a Gavett et al., 2010 Frstl et al., 2010 McKee et al.,2009 Costanza et al., 2011 Stern et al., 2011. The existence of a TBI-AD relationship is well recognized Guo et al., 2000 Jellinger et al., 2001Mauri et al., 2006 Mayeux et al., 1993 Mayeux et al., 1995 Schofield et al., 1997 Tang et al., 1996 Van Den Heuvel et al., 2007b Blyth and Bazarian, 2010 Czonkowska and Kurkowska-Jastrzbska, 2011 Hinkebein et al., 2003 Sivanandam and Thakur, 2012 Verghese et al., 2011,and the overlaps and distinctions between pathological features of AD and TBI, including more recently CTE, have long been the subject of reporting and discussion Tokuda et al., 1991 Graham et al., 1995 Irving et al., 1996 Geddes et al., 1996 Geddes et al., 1999 Jellinger et al.,2001 Schmidt et al., 2001 Smith et al., 2003 Uryu et al., 2007 Dekosky et al., 2007 McKee et al., 2009 Magnoni and Brody, 2010 Johnson etal., 2011 Magnoni et al., 2011 Shively et al., 2012 Johnson et al., 2013 McKee et al., 2013 Omalu et al., 2011. However, the precise nature of how TBI leads to or precipitates AD pathogenesis is not understood. The goal of this proposal is to use molecular level approaches in relevant animal models to identify overlapping profiles between TBI and AD and determine early critical cellular responses to TBI that can be targeted for therapeutic intervention.