Does TBI Affect mtDNA Heteroplasmy?
Abstract
This project seeks to better understand the long-term consequences of traumatic brain injury (TBI) as they pertain to Alzheimer s disease (AD). To accomplish this, we will explore connections between TBI, brain aging, and mutations of the DNA found within parts of cells called mitochondria. As people age, mutations in mitochondrial DNA naturally occur. The long-term accumulation of those mutations may contribute to brain aging, and brain aging is known to put people at greater risk for AD. Researchers now know that when TBI occurs, mitochondria are damaged, although it is not well understood how this plays out over the longer term as TBI survivors grow older. We believe that such damage might be linked to AD, specifically by accelerating the aging-related accumulation of mitochondrial DNA mutations. Overall, a critical mass of research now points to the idea that mitochondrial DNA mutations represent an important (and potentially treatable) link between TBI and late-life risk for AD. In this proposal, we specifically hypothesize that TBI will accelerate the age-related accumulation of brain mitochondrial DNA mutations, and that this will explain the recognized association between TBI and AD. To test this, we will expose young adult mice to a brain injury and then let the mice age. In our first set of experiments (Aim 1), we will determine whether the injury accelerates the age-related accumulation of mitochondrial DNA mutations. In our second set of experiments (Aim 2), we will assess the mice as they age, through a series of behavioral tests and magnetic resonance imaging (MRI) brain scans, and at the end of the study we will collect brain tissue and use it to assess mitochondrial function by measuring the activity of key enzymes. We will then test for correlations between mutations and these behavioral, imaging, and mitochondrial measures. In our third and final set of experiments (Aim 3), we will administer a brain injury to a genetically engineered strain of mice (rTg4510 mice) which accumulate neurofibrillary tangles, the protein clumps that collect in the brains of people with AD. We will then let the mice age, quantify mitochondrial DNA mutations and neurofibrillary tangles in their brains, and test for relationships between these two parameters. We predict that a TBI sustained during young adulthood will increase the amount of brain mitochondrial DNA mutations that are present during old age. We also predict that mutation levels in old age will correlate with functional deficits, MRI measures, and mitochondrial enzyme activity, and that mutations and neurofibrillary tangles will positively correlate. We anticipate that findings from this study will help to explain why sustaining a TBI during young adulthood increases one s late-life risk of developing AD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810497
Entities
People
- Janna Harris
Organizations
- United States Army
- University of Kansas Medical Center