Influence of ApoE Genotype on Tau Elimination from the Brain in Traumatic Brain Injury and Alzheimer s Disease
Abstract
Traumatic brain injury (TBI) is the result of a sudden trauma to the brain that significantly disrupts brain function. While many of the features resulting from the primary trauma tend to subside over time, more chronic events emerge in the aftermath of the initial trauma and evolve over several years or decades. One of the long-term consequences of repetitive head trauma is the development of dementia or Alzheimer’s disease (AD). While AD has always been a concern for our Veterans, the propensity for head injuries sustained in combat has placed our military personnel and Veterans at even greater risk for developing AD than the general population. A prominent pathological feature of both TBI and AD is the accumulation of toxic tau protein aggregates in the brain. Recent studies have indicated these tau proteins can spread from cell to cell, and it is believed that increased levels of tau in the extracellular fluids of the brain play a major role in the progression of certain diseases. In fact, the concentration of tau in brain fluids can be used to predict adverse clinical outcomes following TBI. Likewise, extracellular tau levels in the brain have been shown to predict AD progression and cognitive decline. As such, understanding how tau is processed and eliminated from brain fluids may be important in determining the onset and development of neurodegenerative disease. Another critical factor in the formation of neurodegenerative diseases is possession of the apolipoprotein E4 genotype (apoE4). Numerous studies have acknowledged that apoE4 represents the strongest genetic risk factor for late-onset AD. Likewise, apoE4 has been associated with poorer outcome following TBI, particularly with respect to long-term recovery. Altogether, tau and apoE4 are important drivers of neurodegenerative disease, and understanding the nature of their relationship may determine the association between TBI and the development of AD. It has been observed that tau levels are elevated in the brain when apoE4 is present compared to other apoE genotypes, and several reports have demonstrated a role for apoE in the elimination of extracellular solutes from the brain. Thus, the accumulation of tau in the brain when apoE4 is present may be due to alterations in the removal of extracellular tau from the brain. Our preliminary work observed an effect of apoE genotype on the degradation and elimination of tau from the brain, which may explain the elevated levels of tau in brain when apoE4 is present, and the poor outcome associated with apoE4 individuals in TBI and AD. We propose that apoE contributes to the elimination of extracellular tau in the brain by facilitating tau degradation in a manner similar to that observed for apoE with other brain solutes. Despite the strong presence of tau in both TBI and AD and the correlation between apoE4 and disease outcome, there has been little investigation into the relationship between tau and apoE. The current submission will investigate these concepts and fully explore the influence of apoE genotype on tau disposition in the brain following TBI and in AD. These studies may be particularly meaningful in TBI and AD as they will interrogate an established genetic risk factor (apoE4) and a signature pathological hallmark (tau) for both neurodegenerative disorders. The objectives of the studies proposed in this application are to (1) evaluate the interaction between apoE and tau, (2) determine the effect of apoE on tau degradation and elimination from the brain following TBI and in AD, and (3) examine the association between brain injury and the development of AD. In totality, our studies indicate apoE genotype influences tau elimination from the brain in TBI and AD, which may be an important factor in tau pathogenesis and neurodegeneration, and could explain the association between head trauma and the development of AD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910344
Entities
People
- Corbin Bachmeier
Organizations
- Roskamp Institute
- United States Army