Jie Shen, Ph.D.
Brigham and Women’s Hospital
Boston, Massachusetts

2004 Investigator-Initiated Research Grant

The majority of cases of the rare inherited form of Alzheimer’s disease are associated with mutations in the PS1 gene. This gene is the biological blueprint for the production of a protein called presenilin-1. Researchers have identified a number of possible PS1 mutations, but it is not clear how a PS1 mutation contributes to a breakdown in cell-to-cell communication and memory impairment associated with Alzheimer’s disease.

Jie Shen, Ph.D, and colleagues are exploring this issue in mice. In previous studies, they found that mice with disabled PS1 genes experienced memory problems associated with regions of the brain affected in Alzheimer’s disease and impairments in cell-to-cell communication networks. These problems were followed by a loss of brain cells that progressed with age.

In the current work, the investigators will study mice carrying a human PS1 gene with an Alzheimer-related mutation to test the hypothesis that PS1 mutations cause a loss of cell-to-cell communication function. They will assess memory changes with behavior tests designed for mice. They will also use technologies that enable them to assess the sending and receiving of signals between cells to detect possible impairment in this function. Brain autopsies will be used to assess degeneration and loss of cells.

The data will be used to characterize how a PS1 mutation is manifested in cellular dysfunction and the development of symptoms. A clarification of such mutation-associated brain changes may reveal key steps in “universal” Alzheimer’s disease processes.