ProNGF and Mechanisms of Neurodegeneration in Aging and Alzheimer's Disease
Description: Memory loss and dementia are major medical and socioeconomic problems for the world's aging population. The specific neurons that degenerate with age and cause memory loss include a group of brain cells called basal forebrain cholinergic neurons (BFCNs). Why and how these neurons lose function with age is unknown. BFCNs depend upon pro-nerve growth factor (proNGF), a small but essential protein found in the brain and nervous system that regulates neuronal function and survival. We previously demonstrated that proNGF is found in the brain, that it is essential for BFCN function, and that it is taken up by receptors on BFCNs that transport proNGF to the cell body to maintain BFCN survival. In the aging brain and in Alzheimer's disease, proNGF receptors are lost, proNGF is not transported and accumulates, and this accumulation correlates with neurodegeneration and cognitive decline. In this application, we propose to study why BFCNs lose their receptors, and how this leads to neurodegeneration and memory loss. We propose that oxidative stress, which increases in aging and Alzheimer's disease, inactivates an enzyme necessary to maintain one of proNGF's two receptors. We also propose that as a result, excessive binding to the other proNGF receptor causes BFCN neurodegeneration and cognitive decline. Our research will use novel cell culture and mouse models of aging and Alzheimer's disease to study how aging and Alzheimer's disease compromise proNGF receptors and transport, and the roles of receptor loss and defective proNGF transport in neurodegeneration. The overall goal of our research is to restore degenerating neurons and prevent cognitive decline. Understanding how proNGF receptors are damaged by age and disease, and how this causes neurodegeneration, will provide new understanding and new targets for therapeutic intervention for aging and neurodegenerative disease. This knowledge will thereby promote advances in health care for older Canadians.
Amount: CA$1,239,000
Funding type: research
Funder scheme: Project Grant
Start date: 2023-10-01
End date: 2028-09-30
Investigator: Margaret Fahnestock
Institution: McMaster University
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Funded outputs count: 1
Funder award ID: 190135_1
OpenAlex ID: G8065636867