Role of B Cells and Adaptive Immunity in Exacerbated Alzheimer s Disease After Traumatic Brain Injury
Abstract
Over five million Americans suffer from Alzheimer’s disease (AD) and related dementias (ADRD). According to the Centers for Disease Control and Prevention (CDC), by 2060, the burden of AD and ADRD is projected to grow to 13.9 million people in the United States, which amounts to a staggering 3.3 percent of the population. Alarmingly, the most common risk factor for AD and ADRD is prior central nervous system injury, including traumatic brain injury (TBI). Suffering from a mild to moderate TBI increases the risk for AD 2.3-fold, and a severe TBI increases the risk for AD 4.5-fold. Of great concern is that fact that in the United States, there are millions of TBIs each year, and TBIs are the signature wound for all of the recent conflicts involving our military. Thus, TBI is a major risk factor for AD in military, Veteran, and civilian populations. TBI causes a rapid inflammatory response immediately after injury and efforts to dampen inflammation in AD are ongoing, but to date these efforts have not resulted in effective therapies. While vast numbers of studies identify inflammation and neuroinflammation as hallmarks of AD, it is unknown how inflammation after TBI might facilitate or accelerate the onset of AD. B cells have recently been shown to be required for the development of AD-associated neuropathology and cognitive decline in three mouse models that are genetically programmed to develop AD. The absence or deletion of B cells in these studies prevented the onset of key characteristics of AD, indicating that therapeutic depletion of B cells inhibits AD in mice. A unique aspect of our research is that we identified a rapid post-TBI immune response that is associated with the expansion of B cells that are pro-inflammatory. Importantly, in our studies, the deletion of B cell or specific B cell subsets also prevented the TBI-induced neurodegeneration. Thus, we propose deleting B cells following TBI to determine if removing TBI-activated B cells will prevent or delay the onset of AD in our mouse model. This work has the potential to benefit individuals affected by AD/ADRD, their caregivers, and their families, by revealing important insight into the role of B cells and specific B cell subsets, in TBI-associated AD and ADRD. This research also has the potential to identify a new therapeutic approach for the treatment of AD/ADRD, including depression and cognitive decline, which are often seen following a TBI, and preceding the onset of AD/ADRD. The fact that strategies are already present in the clinic to manipulate these and other classes of immune cells for other neurological diseases suggests that, if validated, there could be significant short-term and long-term impact on the lives of countless civilian, military Service Members, Veterans, and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210690
Entities
People
- Lee Shapiro
Organizations
- Texas A&M Health Science Center
- United States Army