Alzheimer’s disease (AD) is the most important cause of dementia in the United States. It is characterized by the accumulation of two proteins in the brain, amyloid beta (Aβ) and tau. While Aβ accumulation is necessary for the AD process, the accumulation of tau is linked with cognitive decline, as well as nerve cell loss/damage. Utilizing mouse models of this process, we have found that the major genetic risk factor for AD, apolipoprotein E (APOE), is involved in the nerve cell damage, nerve cell loss and cognitive decline linked with tau accumulation in the brain. We now have found that APOE produced by a specific cell type in the brain called astrocytes are key in leading to this nerve cell damage. This provides a novel target for future therapy development. In addition, this APOE linked process is associated with the buildup of certain types of lipids and cholesterol in the brain. We now are trying to determine ways to get rid of this buildup as a potential therapy to block tau-induced damage in the brain.
2017, 2018, 2020
The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer’s disease. APOE4 increases risk and APOE2 decreases risk. The Holtzman lab recently found that, in addition to the effect of APOE on amyloid beta, APOE exacerbates tau pathology and tau-mediated brain damage. We have preliminary data that APOE produced by a particular cell type in the brain called astrocytes is intervening APOE4-mediated brain injury. One goal of the current grant is to better characterize how APOE4 derived from astrocytes is leading to tau-mediated brain injury via another glial cell type called microglia. Recently, we have found that specific types of lipids and cholesterol accumulate in microglial cells in the presence of APOE4 and tau pathology. We think this lipid accumulation may be detrimental to the brain. A second goal of this grant is to better characterize these APOE4-mediated changes in lipids and cholesterol as well as to determine whether decreasing this lipid/cholesterol accumulation will ameliorate tau-mediated brain injury.