Investigating the Impact of BAG3 on Alzheimer-Like Pathology and Cognitive Deficits Associated with Traumatic Brain Injury
Abstract
Traumatic brain injury (TBI) in military personnel and other individuals often leads to an increased risk for developing long-term health problems including the Alzheimer’s disease (AD) and other AD-related dementias (ADRD). AD is the most common form of dementia in the elderly with an estimated 5.7 million Americans of all ages living with Alzheimer s dementia in 2018. It is the fifth leading cause of death among those age 65 and older. Unfortunately, there is no effective prevention or treatment for patients with AD and ADRD. Moderate and severe TBIs and even mild TBI (mTBI) without loss of consciousness are found to be associated with the increased risk of dementia. However, why TBI induces AD-like pathology, especially one major pathological hallmark of AD, i.e., tau aggregation, and the problem in learning and memory remains unknown. Large-scale transcriptomic analysis can reveal the molecular determinants underlying why some neurons are particularly prone to form tau aggregation and degenerate in the context of TBI and AD. Using this analytical method, we have identified some intrinsic hub or master regulator genes (e.g., BCL2 associated athanogene 3, BAG3) that may regulate tau protein aggregation and explain why excitatory neurons are particularly impaired by tau aggregation. We will continue to analyze publicly available large-scale transcriptomic data from the postmortem brains of human healthy cases, human TBI cases, human AD cases, and mouse brains with TBI. The analysis will reveal the transcriptomic changes including those hub genes in the context of TBI. Given the important role of BAG3 in the clearance of tau aggregates, we will visualize the temporal and spatial distribution of tau aggregates, BAG3, and cell-type-specific markers in the transparent mouse and human brain tissue in a three-dimensional manner. We will also determine whether the changes of BAG3 protein level will affect the AD-like pathology and learning and memory issues induced by TBI in animal models. The long-term goal of this project is to identify why some individuals with the history of TBI develop AD/ADRD in their late life. Understanding why TBI can induce tau protein aggregation and neurodegeneration will provide mechanistic insight into the mechanisms underlying the neurodegeneration in TBI and its associated AD/ADRD. A better understanding of the biology of master regulator genes like BAG3 is likely to lead to more directed and specific therapeutics for the prevention and/or treatment of TBI and TBI-associated AD/ADRD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910309
Entities
People
- Hongjun Fu
Organizations
- Ohio State University
- United States Army