Neuronal Mechanisms Driving Synapse Loss in Alzheimer’s Disease

In Alzheimer’s disease (AD), one of the biggest reasons people experience memory and thinking problems is because the connections between brain cells (synapses) get weaker and disappear. Previous research suggests that immune cells and support cells in the brain are responsible for this loss. One reason these cells might be removing these connections is because of a stress signal (called phosphatidylserine, or PS) on the outside of synapses. Normally, this signal is hidden inside the cell, but when the cell is stressed, it can flip to the outside. Studies have shown that when the interaction between this stress signal and immune and support cells is blocked, the loss of synapses is reduced.

We are trying to understand how this stress signal shows up on the brain cells. My team has developed an innovative technology platform to comprehensively identify the underlying mechanisms. Our pilot studies already have uncovered first factors. In the proposed research, we will characterize these factors and also conduct a genome-wide screen to comprehensively identify molecular mechanisms controlling PS exposure at synapses, which are potential therapeutic targets in AD.