Characterizing Protective Effects of Induced Tau Reduction

Tau may serve as an excellent treatment target in Alzheimer’s disease Alzheimer’s disease, and we recently found that genetic elimination of tau had a strong protective effect in mouse models of Alzheimer’s disease. In those studies, tau was absent in the animals starting at conception, and throughout their lives. The proposed research will address the critical question of whether reducing tau expression in adulthood, which is more relevant therapeutically, has similar protective effects.

Alzheimer’s disease Alzheimer’s disease researchers are searching intently for new strategies to treat this disease, with much effort devoted to reducing levels of the “amyloid beta” peptide that is believed to cause the disease. We recently identified a strategy in mouse models of Alzheimer’s disease to make the brain resistant to amyloid beta, by genetically eliminating a protein called tau. We believe that tau reduction, or finding drugs that accomplish the same downstream effects, could be a useful strategy for treating Alzheimer’s disease. In the mice that we have studied, however, tau was absent throughout life, so we don’t know yet if tapping into this strategy in adults would be safe or effective. The goal of this project is to characterize a second-generation line of mice that we are developing, in which tau reduction can be triggered at any stage of life by administering a specific drug. Our goal in the present study is to induce tau reduction in adult mice, and to determine if this can be accomplished without adverse effects and with the beneficial effects that we see when tau is absent from conception. After inducing tau reduction in adult mice, we will perform tests of general health, learning and memory, motor coordination, and other brain functions, and will also examine brain architecture under the microscope, to ensure that no major side effects have occurred. Then, we will determine if the brains of these mice are resistant to the kinds of abnormal brain activity that we observe in Alzheimer’s disease mouse models, as we know mice lacking tau from birth are. These studies will address one of the major issues on the way to translating our success in preventing deficits in mouse models into a tractable strategy for patients with or at risk for Alzheimer’s disease.