Cellular Prion Protein: a potential biomarker of TBI

Abstract

Traumatic brain injury (TBI) is considered a silent epidemic affecting millions of people worldwide. Mild TBI (mTBI) is especially a concern as it is the most prevalent form of TBI suffered by individuals who participate in high-contact sports or even the military. Recently, clinicians have emphasized assessing concentration of proteins within biological fluids that can serve as surrogate biomarkers of TBI. Many proteins have been investigated, but none has examined the cellular prion protein (PrPC), which is expressed abundantly along the extracellular domain on plasma membrane lipid rafts within the central nervous system, and is associated with various important functions. Furthermore, there is mounting evidence that PrPC release from the CNS may be indicative of neurodegeneration, neurotoxicity, and dysregulation of normal signaling pathways, all of which are staples of TBI. Given PrPC’s extracellular attachment, it is possible that mechanical stretching and shearing forces due to head impact, acceleratory forces to the head, or even oscillating blast exposure can result in PrPC dislodgement allowing it to collect within the systemic circulation. Moreover, sustained secondary injury mechanisms such as neuroinflammation and oxidative stress for example are known to upregulate PrPC and even cause its release potentially leading to prolonged elevation of plasma PrPC concentration following TBI. Using an advanced blast simulation apparatus, anesthetized adult Sprague-Dawley rats were subjected to head-only exposure to helium gas-driven primary blast wave of varying intensities. Plasma samples were collected 24 hours following blast exposure and assayed for PrPC analyte concentration as well as being used for comparative immunoblotting against other TBI biomarkers. Furthermore, pre-clinical human plasma samples were collected from athletes following concussion to be analyzed for PrPC concentration against baseline samples collected during the offseason as well as non-athlete controls. Plasma PrPC concentration values were determined by sensitive quantification using a PrPC-specific enzyme linked immunosorbent assay (ELISA) and found that PrPC levels are increased following blast exposure, and partly mitigated by protective head covering. Likewise, human samples show that PrPC plasma concentration shows an increased trend following concussion and are significantly elevated when compared to overall normal values. The results demonstrated within this thesis demonstrate that PrPC is a potentially novel biomarker for detection of TBI and further alludes towards the protein’s involvement in the complex TBI pathology.