Elucidating the Effect of APOE4 Expression on Tauopathy in the EC

Background The apolipoprotein E (APOE) gene provides instructions for making ApoE, a naturally occurring protein believed to help carry fats throughout the body. There are several genetic variations of APOE, including APOE-e2, APOE-e3 and APOE-e4. Individuals who possess APOE-e4 are at an increased risk for developing Alzheimer’s, compared with those who possess other APOE variations. Scientists are trying to understand the exact biological mechanisms linking APOE-e4 and Alzheimer’s risk. Some studies show that APOE-e4 is associated with high levels of abnormal tau protein in the brain. The brain cell’s energy and nutrient transport system is organized in parallel strands like railroad tracks. These tracks allow nutrients to travel across the cell, delivering key materials to the cells, providing them with energy and keeping them healthy. The tau protein helps keep these tracks straight. However, in Alzheimer’s and other brain diseases like frontotemporal dementia and Pick’s disease the shape of tau protein becomes modified and this could contribute to tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. One of the first brain regions impacted by abnormal tau during Alzheimer’s is the entorhinal cortex (EC), a region important for memory. However, it is not entirely clear how or if abnormal tau is transported from the EC to other brain regions, or how APOE-e4 may contribute to this process. In preliminary research, Dr. Tal Nuriel and colleagues have found that genetically engineered Alzheimer’s-like mice with human APOE-e4 show abnormally high brain cell activity in their entorhinal cortex, and that this activity can promote the transportation of tau to other brain regions. The researchers also observed significant damage to certain EC brain cells, in these mice. Taken together, based on these findings, Dr. Nuriel believes that one possibility could be that APOE-e4 “overactivates” the EC and that the brain cells in the EC region may be more likely to release abnormal tau protein. Research Plan Dr. Nuriel and colleagues will study the links between APOE-e4, abnormal tau and brain damage. Their effort will involve a detailed analysis of how the e4 genetic variation impacts brain cell activity in the EC. The researchers will use sophisticated genetic techniques to analyze the “transcriptome” (or the complete instructions for which genes should be turned “on” and “off”) in EC brain cells from genetically engineered mice with either the APOE-e3 or APOE-e4 genetic variation. Additionally, Dr. Nuriel’s team will analyze the transcriptome of cells from another brain region in the mice, called the primary visual cortex (PVC), a brain region known to resist damage by abnormal tau and other features of early Alzheimer’s. Using advanced computational techniques, Dr. Nuriel’s team will then compare how APOE-e4 may impact genetic activity in the different cell types, and how these differences may make EC cells more likely to become over-activated and promote nerve cell damage as well as the movement of abnormal tau to other brain regions.