Identification and Characterization of Alzheimer s Disease-Associated Protein Misfolding Seeds After Traumatic Brain Injury
Abstract
Traumatic brain injury (TBI) resulting from car accidents, contact sports, and military duty can result in bruising, torn tissues, bleeding, and other physical damage to the brain that can result in long-term complications or even death. Chronic traumatic encephalopathy (CTE) is a progressive degenerative disease of the brain found in athletes and others with a history of repetitive brain trauma that is characterized by the aggregation and deposition of the tau protein. In addition, a history of TBI is a strong risk factor that can initiate molecular cascades promoting the development of Alzheimer’s (AD). However, the cellular and molecular bases by which TBI contributes to AD or CTE are unknown. AD is characterized by the progressive formation of amyloid-beta (ab) plaques and neurofibrillary tangles (NFTs) composed by hyperphosphorylated tau (ptau). Multitude of studies have shown strong evidence for the concept that the misfolding, aggregation, and brain accumulation of protein aggregates such as ab and ptau are a triggering event in the pathogenesis of this disease. Importantly, recent results from our group and others have shown experimental evidences for the pathological spreading of misfolded proteins associated to neurodegenerative diseases. Our main goal is to study the effect of single-acute and repetitive-mild TBI on the initiation of AD or CTE pathologies and to study the properties of the produced misfolded tau aggregates. We want to determine whether TBI events are able to trigger the misfolding and aggregation of amyloidogenic tau, which will then propagate the pathology throughout the brain, inducing the inset and development of the disease. To that end, we will determine the effect of single acute and repetitive-mild TBI on spreading and progression of brain pathology in mice models. After the traumatic event, mice will be analyzed at various intervals after initial TBI and quantity, localization, and distribution of protein aggregates will be evaluated. In addition, we will analyze the molecular and biological properties of misfolded proteins produced as a result of single-acute and mild-repetitive TBI. We will investigate in detail the properties of the aggregated proteins produced by TBI and their capability to accelerate the pathology associated to the disease. In an effort to analyze the mechanisms involved in tau aggregation after TBI, we will also study tau formation in neuronal cultures that will be stretched to mimic TBI in cultured cells. This proposal focuses on elucidating the mechanism by which TBI is associated to the development of AD or CTE. Given the high frequency of TBI in the population, our findings may help to understand the mechanism for a highly significant risk factor for AD and would likely open novel strategies for therapeutic intervention to either minimize the initial alterations produced by TBI or to block the spreading of the pathology that will subsequently lead to neurodegeneration. Since various other brain disorders are characterized by the accumulation of misfolded aggregates that spreads throughout the brain, this project may also serve as a starting point to understand the effect of TBI in other neurodegenerative diseases associated to protein aggregation.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710632
Entities
People
- Ines Moreno Gonzalez
Organizations
- United States Army
- University of Texas Health Science Center at Houston