Impact of APOE Genotype on Astrogliopathies in Repetitive mTBI
Abstract
Traumatic brain injury (TBI) is a major cause of morbidity among military and civilian populations. Among the Soldiers who survive conflicts in Iraq/Afghanistan, TBI accounts for 11%-23% of their casualties, more than any other war in recent U.S. history. From 2000-2014, for all TBIs diagnosed in U.S. military personnel, 82.4% were classified as mild TBI (involving vehicle crashes, falls, sports and military training activities), with 50% resulting from multiple head injuries. Similarly, 80% of civilian TBIs arise from mild TBI. It is estimated that >5 million Americans are living with disabilities from TBI, which is a long-standing risk factor for Alzheimer’s disease and related dementias (ADRD). Mild TBI (particularly repetitive mild TBI [r-mTBI]) is now recognized to be a major health concern, with apparent cumulative effects of mTBI on neurological outcomes. A distinct pathological feature of r-mTBI is the abnormal build-up of a toxic form of the protein tau in astrocyte cells in the brain – termed tau astrogliopathies. Astrocytes play many important roles in brain health, including maintenance and support of the blood-brain barrier, neurotransmitter signaling, and repair of damaged tissue, and these functions may be compromised by astrogliopathy. These astrocyte lesions are also observed in advanced age-related tau astrogliopathy (ARTAG), and several variants of frontotemporal dementia (FTD), and have been suggested to be a prominent precursor to TBI-induced neurodegeneration. The precise nature of how TBI leads to or precipitates these astrocyte lesions is not understood. Why do some individuals develop astrogliopathies consistent with ARTAG or FTD, while others do not? How do these lesions impact on the ability of astrocytes to support normal neuronal and vascular functions in the brain? What influences act on TBI neurodegeneration to allow emergence of features reminiscent of ARTAG, FTD, or related conditions? Apolipoprotein E (ApoE) is a protein involved in fat metabolism that, in the brain, is primarily produced by astrocytes. The protein is encoded by the APOE gene for which there are three common forms (alleles), one of which (APOE4) is the most common risk factor for AD, and has been implicated to increase severity of other ADRDs such as FTD. APOE4 allele also confers an increased risk for poor outcome after TBI. This may indicate a relationship between APOE genotype and astrocyte function, but this, and the possible influence of APOE genotype on promotion of TBI-dependent astrogliopathies, is unknown. Clinical studies in TBI patients are insufficient at this time to answer these questions and are hampered by the variation inherent in any population studies (age, gender, ethnicity, history), as well as the diversity of ways in which a TBI, or TBIs, can be sustained. They are mostly inadequate however because of our inability to examine molecular level TBI consequences in the brain during life, restricted as we are to a single time point of investigation at autopsy. Thus, we must turn to animal models in which we can profile the brain’s response to injury over time. We have spent years developing and characterizing mouse models of r-mTBI that demonstrate lifelong neuropathological features of human TBI and are thus relevant models in which to generate data that will translate to patients. Our data clearly demonstrate the unique and lasting contributions of astrocytes, as well as inflammatory cells termed “microglia,” to pathological sequelae of TBI, in both animal models and human patients; thus, these cell-specific changes represent potentially critical targets for therapeutic intervention. Our data also suggest that APOE genotype influences TBI-induced astrocyte and microglia pathobiology. Given the key role for astrocytes in supporting brain physiology, we hypothesize that this is disrupted by TBI, exacerbated by APOE4 genotypes, and this disruption persists long after the original i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010281
Entities
People
- Fiona Crawford
Organizations
- Roskamp Institute
- United States Army