Contribution of Thrombin Signaling to Alzheimer s Disease Pathology Following Traumatic Brain Injury (TBI)
Abstract
Alzheimer’s disease (AD) is the most common form of dementia. In 2019 there were an estimated 5.8 million Americans with AD, and that number will continue to rise as the population age rises. The healthcare costs related to AD are staggering, with an estimated $290 billion attributed to AD-related health care. AD is a progressive, neurodegenerative disorder that is primarily characterized by profound memory loss and loss of other cognitive functions. To date, there are highly limited treatment options for individuals with AD. Most of these options only help to alleviate symptoms or slow decline, but they do not stop the underlying pathology and they do not work for all people with AD. As such, there is an urgent push to better understand the causes of AD in order to inform novel, improved therapeutic techniques. There are two forms of AD, early-onset AD that is caused by specific, inherited genetic mutations, and the more common late-onset AD (LOAD). The causes for LOAD remain unclear, but an increased risk for developing AD has been linked to a number of factors, including lifestyle, genetics, and environment. One such risk factor for LOAD is prior incidence of traumatic brain injury (TBI). Like AD, TBI is a prominent health condition, with an estimated two million people suffering from a TBI each year. Along with many other serious and long-term consequences faced by individuals who suffer from a TBI, TBI is considered a major risk factor for AD and related dementias, with mild to moderate TBI increasing the risk of AD 2.3-fold, and severe TBI increasing the risk 4.5 fold. Therefore, it is essential to study the possible underlying factors that connect TBI and AD in order to develop better strategies for reducing the likelihood of developing AD and related dementias following TBI. When healthy, the brain is protected by a system of blood vessels, known as the blood-brain barrier. Damage to these blood vessels has been identified in the brain of individuals with both AD and TBI. This suggests that damage to the function of brain blood vessels may be a link between TBI and subsequent development of AD. Thrombin is a blood-based protein that has a number of functions. Thrombin signaling can lead to increased inflammation and cell death. Importantly, thrombin may enter the brain when there is damage to the brain blood vessels, like that found in TBI. Accordingly, increased thrombin has been identified in both AD and TBI. Therefore, thrombin may be a common factor that regulates the progression of AD-related pathology following TBI. Our previous work has shown that blocking thrombin signaling activity can be beneficial in an animal model of AD. This includes improving function of the brain blood vessels and reducing inflammation. Unfortunately, thrombin is the main driver of the blood clotting process, and directly inhibiting thrombin could increase bleeding risks following TBI. An alternative treatment strategy is reducing thrombin signaling activity by blocking activation of the thrombin receptor. In animal models of TBI, blocking thrombin activation of its receptor has improved amnesia and depression-associated behaviors. Therefore, the purpose of the current proposal is to determine if thrombin signaling following TBI plays a key role in the subsequent development of AD and related pathology. In order to accomplish this goal, we will utilize a widely accepted model of TBI in a well-established mouse model of AD. We will test whether blocking thrombin activation of its receptor after TBI improves outcomes related to AD, including markers of depression, cognitive function, inflammation, and AD-related protein accumulation. We will additionally investigate whether blocking thrombin signaling protects the function of the brain blood vessels after TBI. This work may help to reveal novel mechanisms for AD pathological development and may lead to the development of better therapeutic strategies that target multiple aspects
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210280
Entities
People
- Jaclyn Iannucci
Organizations
- Texas A&M Health Science Center
- United States Army