Why do we still have such limited treatments for Alzheimer’s disease (AD)? One major reason is that AD mouse models do not cover the important step that leads from increasing amyloid plaques to the development of tau tangles. There have been improvements, and the recently developed “APPKI” mice now model plaque development in a manner much closer to the human disease progression. Our previously funded CureAlz study produced a detailed database of gene expression in these models throughout life and aimed to analyze the effect of bringing the APPKI mice even closer to the human condition by adding normal human tau. We found that the addition of human tau weakened several protective mechanisms in the mouse immune system and accelerated age-related changes likely to decrease the function of mitochondria, the energy-producing engines of the brain. These differences suggest points at which the resistance of humans to the clinical phases of Alzheimer’s disease could be improved. Our proposed studies will validate these changes further, both morphologically and functionally.
We also now are looking at these gene expression changes in a regional and cell-specific manner to pinpoint the differences between the effects of mouse and human tau in response to plaques. In addition, we are adding a version of a gene that we know increases the risk of Alzheimer’s disease in humans, with the aim of further compromising the mouse immune system and developing a full model of disease in which rising plaque load in the mouse leads to the later clinical phases of the disease. Such a model would provide a leap forward in our analysis of how to prevent this devastating condition.