Grant: Project Grant

Alzheimer's disease is a major medical and socioeconomic problem for the world's aging population. However, there are large gaps in our understanding of its basic biology. One of those gaps concerns nerve growth factor, a small but essential protein found in the brain and nervous system that regulates cell-cell communication, neuronal function and survival, and repair after injury. We were one of the first labs to demonstrate that its protein precursor, called proNGF, is the predominant form in the brain and that it has biological activity. In the healthy brain, proNGF is taken up by neurons that need it and transported to the cell body. In Alzheimer's disease, proNGF is not taken up and accumulates, and this accumulation causes neurodegeneration and correlates with cognitive decline. The mechanisms causing abnormal proNGF accumulation are not well understood. In this application we propose to study the mechanisms by which proNGF is transported within the particular neurons that are vulnerable in aging and Alzheimer's disease and that are crucial for learning and memory. Our proposed research will use novel cell culture approaches and mouse models of aging and Alzheimer's disease to study the roles of receptor loss and defective proNGF transport in neurodegeneration, and how aging and Alzheimer's pathology compromise proNGF transport. The overall goal of our research is to prevent cognitive decline. Understanding how proNGF is transported within the cell and how that transport is compromised is relevant to the molecular mechanisms of cognitive decline in aging and Alzheimer's disease. This project will provide new understanding and new targets for therapeutic intervention for neurodegenerative disease and aging and may allow us to restore degenerating neurons and their connections. This knowledge will thereby promote advances in health care for older Canadians.