2023 Alzheimer's Association Clinical Scientist Fellowship to Promote Diversity (AACSF-D)
Effect of glial ApoE on TBI and tau-mediated neurodegeneration
How does APOE produced by support cells affect Alzheimer’s brain changes after head injury?
Enmanuel Perez, M.D., Ph.D.
Washington University
St. Louis, MO - United States
Background
Traumatic brain injury (TBI) results from an injury to the head that disrupts normal brain function. Studies suggest that TBI may impact an individuals later life risk for Alzheimer’s and other brain diseases by affecting tau. Tau is a protein that supports brain cells, and it becomes modified or “misfolded” in many different brain diseases, ultimately leading to nerve cell death in the brain.
The apolipoprotein E (APOE) gene makes ApoE protein, which helps carry fats throughout the body. There are several APOE gene variations, including APOE-e2, APOE-e3 and APOE-e4. Possessing the APOE-e4 variation is thought to impact some populations’ risk of developing Alzheimer’s. Individuals with APOE-e4 also have an increased Alzheimer’s risk after TBI. In the brain, APOE is mainly produced by support cells called astrocytes. However, immune cells in the brain (microglia) can also create APOE in the brain. APOE and microglia both contribute to nerve cell death in mouse models of Alzheimer’s, but the specific contribution of APOE produced by microglia to brain cell death following TBI is not well understood.
Research Plan
Dr. Enmanuel Perez and colleagues aim to investigate the role of APOE in nerve cell death after TBI. The researchers will use a genetically engineered Alzheimer's-like mouse that contains APOE and induce different types of TBI. Mice will undergo TBI at 3-6 months of age and be cognitively assessed 1 or 3 months later. The researchers will assess brain cell death after TBI by measuring the size of different brain regions. Further, Alzheimer’s brain changes will be examined by staining for modified tau protein. The researchers will then investigate how different types of APOE affect support cells in the brain, such as astrocytes and microglia by measuring the amount of “activated” support cells after TBI by staining for specific protein markers. They will also measure differences in gene expression within different cell types in the brain.
Previous work by this group has shown that a shift in APOE production from astrocytes to microglia contributes to brain inflammation and nerve cell death. However, how APOE produced from different cell types alters the effects of TBI is unclear. The researchers believe that TBI causes “activation” of microglia, causing them to produce APOE, which will accelerate nerve cell death. They will test this by selectively removing APOE from astrocytes or microglia in an Alzheimer’s mouse model and measuring the effects on brain health.
Impact
The results of these studies will elucidate the effects of APOE production on brain inflammation and nerve cell death after TBI. The findings could also reveal new therapeutic targets for TBI treatment.