Grant: Operating Grant

Neurotrophins are small but essential proteins found in the brain and nervous system that govern critical aspects of cell-cell communication, neuronal function and survival, and repair after injury. We were one of the first labs to demonstrate that protein precursors called proneurotrophins are the predominant form of these molecules in the brain and that they have biological activity, although the nature of that activity is now hotly debated. In Alzheimer's disease, one of these proneurotrophins, proNGF, accumulates in areas of the brain necessary for cognition, learning and memory, and this accumulation correlates with cognitive decline. The mechanisms causing abnormal proNGF accumulation and how that affects neuronal function are not well understood. In this application we hypothesize that the survival- or death-promoting activities of proNGF depend upon the balance of receptors present, that proNGF is transported within neurons from axon terminal to cell body and that it supports cell body survival. Moreover, we propose that when one of the receptors is lost in aging and in Alzheimer's disease, proNGF is no longer transported, accumulates and becomes harmful to neurons. Our proposed research will use cell culture approaches to examine the biological effects of proNGF accumulation and elucidate the roles of receptor loss and defective proNGF transport and signalling in neuronal degeneration. Understanding the conditions under which proNGF causes survival or death, and how it signals and is transported within the cell, is important to our basic knowledge of the normal nervous system and to the molecular mechanisms of cognitive decline. The overarching goal of our research is to prevent cognitive decline. This project will provide new understanding and new targets for therapeutic intervention for aging and neurodegenerative disease and will thereby promote advances in health care for older Canadians.