Next-Generation Humanized Mice to Investigate How TBI Interacts with Genetic Risk Factors to Trigger Dementia
Abstract
It is well documented that a history of traumatic brain injury (TBI) increases the risk of developing dementia later in life. In Veterans, the risk of developing Alzheimer’s disease correlates with the severity of TBI. The relationship between TBI and dementia is still poorly understood. But the timeframe of many years between a TBI and developing cognitive symptoms of dementia affords the possibility of interventions to prevent this catastrophic outcome. However, there are challenges to be overcome if we are to exploit this opportunity: (1) We need to know how pathological elements involved in the development of AD interact. (2) We need biomarkers to be able to identify people that are headed towards AD and to evaluate their response to treatment. (3) We need to develop clinically relevant animal models to study the mechanisms and causal relationships whereby TBI leads to AD and for the eventual development and preclinical testing of therapeutic strategies. Alzheimer’s disease and TBI share many features in common. For example, AD is characterized by a buildup in the brain of aggregated proteins. Interestingly, similar forms of aggregated proteins can be triggered in the brain by TBI. Could TBI early in life initiate pathological changes in aggregated proteins that accelerate AD? Inflammation is also a central player in both AD and TBI. The aging immune system becomes progressively dysregulated showing higher baseline levels of pro-inflammatory markers that lead to abnormal and inefficient activity. Thus, in the aged brain, aggregated proteins that might otherwise be cleared are allowed to accumulate in toxic levels. Remarkably, these aggregated proteins can further disturb brain inflammatory responses. Could TBI lead to a dysregulated inflammatory response that allows for aggregated proteins to go unchecked? Another point of intersection between AD and TBI lies in a class of brain cells or neurons in the brain that signal using the neurotransmitter acetylcholine. These cholinergic neurons are very important for learning and memory, and loss of these brain cells has been identified in both AD and TBI. The interrelationship between all these elements is evidenced by the fact that protein aggregations may cause these brain cells to malfunction and dysregulate brain inflammation. Moreover, a final link between AD and TBI that we consider in this application is the genetic risk conferred by a gene named APOE4. Having the APOE4 gene greatly increases the risk for AD and worsens outcomes after TBI. Not surprisingly, APOE4 is involved in clearance of protein aggregation and inflammation. This application brings together Principal Investigators Dr. Arthur Brown, who studies neurotrauma in mice and rats, and Dr. Marco Prado, a dementia expert, who has generated new mouse models of dementia to study high-level cognitive dysfunction. This application makes use of: (1) A clinically relevant model of TBI that mimics in the mouse brain the stretching of the brain that happens in humans during TBI. (2) Mice in which the key components of genetic risk and protein aggregation have been ‘humanized,” i.e., their DNA sequence resemble those of humans, to model critical aspects of human disease. (3) State-of-the-art testing of brain function in mice, using touchscreens similar to iPADs and tests of behavior that are similar if not identical to ones used in humans with dementia. (4) Brain imaging analyses of humanized mice that is similar to brain imaging that can be done in humans with TBI. Our research program will test whether after TBI, APOE4 or reduced cholinergic function accelerates the onset of AD-like cognitive dysfunction and neuropathology in humanized mice and the mechanisms involved. We anticipate discovering ways to predict using imaging or behavioral testing when individuals that suffer TBI will have a higher risk of developing dementia. We also expect to reveal new ways to decrease this risk.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010323
Entities
People
- Arthur Brown
Organizations
- United States Army
- Western University