Mouse and Human Models for Investigating Influences of Tau on Progression of Alzheimer s Disease Following Traumatic Neuronal Injury
Abstract
What is traumatic brain injury? The brain consists of networks of interconnected neurons, which are wire-like cells that communicate electrically. These networks control subconscious processes such as breathing and heartbeat, and also enable individuals to move, sense, and process information. Damage to neurons disrupts these networks; depending on the type of damage, specific functions controlled by the brain can fail, including memory and thought. A particularly devastating variety of damage to the brain is traumatic brain injury (TBI), which occurs when the brain is jolted by an external force. Athletes such as boxers or American football players suffer TBI as a result of the many mild traumatic events accumulated over their careers. In a military context, Soldiers and Veterans often experience TBI as a result of blast injury, such as that caused by improvised explosive devices (IEDs). Because of improvements in armor and battlefield medical care, an increasing number of wounded Warriors survive these blasts. However, as a consequence, these individuals also often develop serious problems in their thinking and behavior. Effects of such trauma are particularly widespread among Veterans of recent wars in Iraq and Afghanistan. In fact, the United States Department of Defense categorizes TBI as the "signature injury" among Veterans from these wars. What does TBI have to do with Alzheimer s disease? One particular disease that often results from TBI is Alzheimer s disease, a chronic incurable degenerative disease of the brain. The most common early symptom of this disease is short-term memory loss, with additional symptoms such as language problems, disorientation, mood swings, and behavioral problems emerging and getting worse over time. Unfortunately, we do not yet understand why individuals develop Alzheimer s disease following TBI. Therefore, this application details a number of experiments that will improve our understanding of how TBI leads to Alzheimer s disease. What questions are our research team trying to understand, and why are the answers important? Our research team hypothesizes that TBI causes Alzheimer s disease by damaging neurons in a two-step process. In the first step, the initial mechanical trauma tears neurons, pulling apart the structural scaffolding of neurons, known as the cytoskeleton. The jolt also tears blood vessels in the brain, releasing toxic chemicals called cytokines and chemokines into the brain, through a process known as neuroinflammation. These toxic chemicals then further damage neurons, resulting in a destructive spiral of increased neuron damage and further release of toxic chemicals, ultimately resulting in broken neuronal networks and cognitive decline. We believe that at the center of this degenerative cycle is a protein called tau, which, in a healthy individual, serves as a reinforcement material, to stabilize struts in the cytoskeleton known as microtubules. Both mechanical damage and chemical damage -- and thus the first and second phase of injury noted above -- can knock tau off of microtubules, causing a neuron to fall apart. By identifying how mechanical and chemical damage causes tau to bind and fall off from microtubules in this application, we can then help to develop drugs and other therapies to prevent damage to neurons, if not during the initial mechanical injury, then during the second stage of neuroinflammation, to break the cycle of degeneration. How is our team answering these questions? To answer these questions, we will use two experimental models. The first is a mouse model of TBI, which will reproduce the response of the brain to traumatic injury in a living system. The second is a human stem cell model; these stem cells are a special variety called induced pluripotent stem cells (iPSCs), which are made from a small piece of skin from an adult individual and can be turned into neurons in the laboratory. These neurons can then b
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510561
Entities
People
- Sameer B Shah
Organizations
- United States Army
- University of California, San Diego