Mechanisms Underlying Amyloidogenic Outcomes Following Injury of Human iPSC-Derived Neurons
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 and incurable degenerative disease of the brain. Symptoms worsen over time, and include memory loss, language problems, disorientation, mood swings, and behavioral problems. Unfortunately, we do not yet understand why individuals develop Alzheimer’s following TBI. And so, we do not have effective therapies to treat TBI-Alzheimer’s or predict who is at risk for disease. This application details experiments that will improve our understanding of how TBI leads to Alzheimer’s disease. What questions is our research team trying to understand, and why are the answers important? One type of TBI is called “mild” TBI and is often called a concussion. The word “mild” is used because injury symptoms seem to disappear within days to a few weeks. However, this term is misleading, because in many cases, hidden damage can linger and progressively erode the brain. Indeed, this form of TBI was highly prevalent in Soldiers of recent wars and is a large burden on military personnel, Veterans, and their families. We believe there is a limited window in which those who have experienced TBI can be successfully treated. Therefore, it is essential to identify those individuals who are most at risk for later disease and also to develop effective therapies to stop or slow down progression to Alzheimer’s. To succeed in these daunting tasks, we must first understand the chain of events that connects mild TBI to Alzheimer’s disease. We hypothesize that mild TBI causes Alzheimer’s disease by causing a cascade of toxic events inside neurons. At the time of injury, mechanical trauma damages neurons, which causes a weakening of the structural scaffolding of neurons, known as the cytoskeleton. Traumatic injury also causes the increased production of sticky versions of neuronal proteins known as “amyloid” and “tau,” which can choke and further weaken neurons and their surrounding cells if they accumulate over time. Damage is amplified with repeated injury, and the end result is a downward spiral of broken neuronal networks and cognitive decline. How is our team answering these questions? To answer these questions, we use a special variety of human stem cells called induced pluripotent stem cells (iPSCs), which are made from a small piece of skin, or a biopsy, from an adult individual. These iPSCs can be turned into neurons in our laboratory. To damage neurons in the lab, we use innovative micro-devices that allows us to very rapidly and very relia
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910315
Entities
People
- Sameer B Shah
Organizations
- United States Army
- University of California, San Diego