Project 458564

The brain cells that are critical for learning, memory, and attention lose function with age and die in Alzheimer's disease, causing memory decline. These cells obtain the proteins they need to survive and function, called neurotrophins, by transporting them from nearby brain areas. In aging and Alzheimer's disease, neurotrophin transport is reduced, which may contribute to brain cell death and decreased memory. It is important to better understand what causes reduced neurotrophin transport to improve brain cell survival and enhance memory. In aging and Alzheimer's disease, there is an increased amount of a harmful molecule called peroxynitrite in the brain. We have recently observed that peroxynitrite decreases neurotrophin transport, but how it does so is unknown. Peroxynitrite decreases the stability of microtubules, the cellular highways that neurotrophins are transported on, and prevents microtubules from interacting with the motor proteins that move neurotrophins throughout the brain. Peroxynitrite may also recruit other proteins that interfere with associations between motor proteins, neurotrophins, and microtubules. However, it is unclear if these mechanisms are responsible for loss of neurotrophin transport. This project will determine how peroxynitrite affects transport of neurotrophins in rat brain cells. First, we observed that adding peroxynitrite to these cells decreases neurotrophin transport. Next, we will determine if neurotrophin transport can be restored by stabilizing microtubules or preventing the action of interfering proteins. If not, other mechanisms will be investigated. Successful treatments will also be tested in aged brain cells and those obtained from a mouse model of Alzheimer's disease to determine if they may be beneficial in aging and Alzheimer's disease. This project may help scientists develop treatments to improve brain cell survival and function to eliminate memory deficits in aging and Alzheimer's disease.