In Alzheimer s disease (AD), critical synaptic connections between neurons disintegrate and cells die. The brains of individuals with AD accumulate plaques of a protein fragment called AÎ that disrupt synapse function and cause neuronal death. Dr. Kennedy and his team will study a protein called netrin-1 that promotes cell survival, synapse formation, and synaptic changes underlying memory. Netrin-1 also binds AÎ and its precursor, Amyloid Precursor Protein (APP). APP acts similarly to netrin-1; however, AÎ does the opposite, disrupting synapses and killing neurons. The team will test the idea that APP is a receptor for netrin-1 at synapses in the healthy brain, but that in AD AÎ steals netrin-1 away from APP, thereby disrupting synapse function. Biochemical techniques, neuronal cell culture, electrophysiology, and live-imaging will be employed to assess the effects of AÎ , APP, and netrin-1 on synapse function. The proposed studies will help to understand how to maintain and promote synapse function in AD.