Alzheimer's disease and dysfunction of the retromer complex: genetic approaches to novel therapeutic targets

In Alzheimer's disease (AD), the function of nerve cells is decreased and the nerve cells die. At the same time, there is an accumulation around the nerve cells of a particular type of material that forms unusual structures termed ‘plaques’ and ‘tangles.’ The production of these plaques and tangles appears to result from a decreased ability of the nerve cells to move material to their proper locations inside the cell. In these cells, the machinery that makes sure that material gets properly located does not work very well. Despite a growing appreciation of the problems that nerve cells have in AD, including the problem of poorly working systems for the movement of material, there are few options today for the treatment of AD. Nerve cells are difficult to work with, but the machinery that nerve cells use to properly locate material is found in all cells. Therefore, we intend to study this machinery in a type of cell that is easier to work with in the laboratory, and that moves material around inside the cell in the same way that nerve cells do. In this way, we hope to acquire knowledge that might be useful in the development of new treatments for AD. Yeast cells have provided a deeper understanding of how human cells work, and what goes wrong in certain diseases; what has been learned from the study of yeast often has direct application to our understanding of human cells. The defect in the system for properly locating material within AD cells can be mimicked experimentally in yeast cells. The advantage of studying this AD situation in yeast is the unequalled capacity to use powerful genetic and molecular approaches to find unexpected ways to make the problems of AD cells less severe. In preliminary experiments, we have identified several ways that yeast cells can be altered to mimic the problem found in AD cells. Starting with this situation, we plan to identify ways that these altered yeast cells can be further altered in additional ways to actually minimize the AD-related problem. From analysis of these altered yeast cells, we will be able to work out how the AD-related problem has been overcome. We hope that this knowledge will eventually be able to guide the search for new therapies to help nerve cells affected by AD.