Investigating the Inflammatory Response to Injury: Examining the Impact of Apolipoprotein E Variants on Drosophila Recovery following Repetitive Traumatic Brain Injury

Abstract

Repetitive traumatic brain injury (rTBI) is a major global health burden that increases an individual’s risk of developing neurodegenerative disorders, including chronic traumatic encephalopathy (CTE) and Alzheimer’s disease (AD). While little is known about the underlying molecular processes associated with adverse outcomes following rTBI, apolipoprotein E (APOE), which mediates lipid transport, is known to impact individual risk of developing neurodegenerative disorders in a variant-specific manner (APOE4 > APOE3 > APOE2). In this thesis, I explore the role of APOE variants in recovery following rTBI using transgenic Drosophila melanogaster strains each expressing one of the three APOE isoforms. Longitudinal outcomes were compared by measuring survival, post-injury locomotor recovery, vacuolization, and proteomic changes. Following five strikes to the head, male fruit flies expressing APOE2 demonstrate prolonged survival following rTBI relative to APOE3, APOE4, and genetic control flies while APOE4 expressing female flies show significantly lower survival than other strains. Trends in locomotor recovery and neurodegeneration also suggest APOE2 is neuroprotective for males while APOE4 leads to decreased recovery for both males and females. Proteomic analysis in male flies one day following injury indicates that baseline differences in metabolism and production of reactive oxygen and nitrogen species, based on the APOE variant, may predispose individuals to neurodegeneration and worsened recovery. This may be regulated, in part, by differences in acute immune activation following injury. Future research should investigate progressive changes in protein expression following injury to determine if persistence of neuroinflammation and metabolic disruption underlies the connection between rTBI and CTE.