Neuropathology and Immune Biomarker Discovery in a Rat Model of Alzheimer s Disease, TgF344-AD, with Single or Repetitive Traumatic Brain Injury
Abstract
The relationship(s) between traumatic brain injury (TBI) and neurodegenerative diseases, such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE), remain poorly understood and markedly understudied. Major barriers to progress in the field include: (1) the lack of available animal models that recapitulate the different types of TBI, (2) the lack of methods for tracking disease progression, and (3) the lack of tools for evaluating new therapeutic strategies. Accumulating evidence suggests that TBI, and especially forms of TBI that are repetitive and moderate (rmTBI), activate neuropathological pathways associated with AD and other types of neurodegenerative diseases, leading to the accumulation of misfolded proteins, loss of function at synapses, death of neurons, inflammation, and decline in cognitive ability. Similar to clinical trials for AD, every promising drug identified in preclinical studies using animal models of TBI has failed in Phase II/III clinical trials. Clearly, animal models that more effectively reflect AD and TBI/rmTBI in humans are desperately needed. Herein, we propose a comprehensive strategy for evaluating AD progression in the context of new rat models of three different types of TBI, including: (1) a single, moderate, unilateral, closed-skull controlled cortical injury (CCI) model (called “1X-CCI/TBI”), (2) a twice repeat, moderate, unilateral, CCI model (called “2X-CCI/TBI”), and (3) a blast repetitive moderate TBI model (“rmTBI”). The results of our experiments will establish metrics for evaluating neuropathology, both in living animals using neuroimaging and postmortem, as well as for identifying cellular responses to CCI/TBI and rmTBI detected as changes in blood protein profiles. Our proposed experiments will also use a novel approach to evaluate neuroimmune signals that are packaged in small vesicles -- called exosomes and microvesicles -- shed from cells of the central nervous system (CNS) and released into the bloodstream. We will use a variety of techniques to analyze cargoes carried by these exosomes and microvesicles as potential “biomarkers” that may serve as metrics to help increase our understanding of the potential connections between TBI and AD. The biomarkers we identify in our proposed studies using the rat models of CCI/TBI and rmTBI are likely to provide key insights into TBI biomarkers in human patients. Our proposed experiments provide new tools (e.g., new rat models of CCI/TBI and rmTBI, new CCI/TBI-, rmTBI-, and AD-biomarkers associated with the peripheral immune system and the neuroimmune system) and metrics that will hasten and/or augment clinical studies. These discoveries will also help move promising drugs more quickly to clinical phases.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710583
Entities
People
- Huntington Potter
Organizations
- United States Army
- University of Colorado Denver