Project 455703

Alzheimer's disease is thought to be caused by abnormal accumulation of amyloid beta proteins in the brain, which lead to neurodegeneration and dementia. However, most people over the age of 70 have amyloid in their brains, but the majority do not develop dementia. In addition, treatments developed to decrease amyloid have not been beneficial in Alzheimer's. This suggests that other critical factors must interact with amyloid to increase the risk of developing Alzheimer's disease. One strong possibility is that a protein named the vesicular acetylcholine transporter is this critical factor interacting with amyloid. This protein-which regulates how effectively a type of brain cell called a cholinergic neuron can communicate with other brain cells-is decreased early in Alzheimer's. We propose that the degree to which this protein changes in cholinergic neurons helps to drive the development of Alzheimer's disease. We will address how disruptions in the vesicular acetylcholine transporter, combined with amyloid pathology, contribute with cognitive dysfunction and degeneration related to the hippocampus, a critical brain region involved in memory and affected early in Alzheimer's disease. In mice which present both amyloid pathology and reductions in the vesicular acetylcholine transporter, we will use novel tools to investigate rapid chemical changes in, and activity of, cells in the hippocampus, while the mice solve touchscreen tests of learning and memory that are the same as those used in human patients. We will also chemically restore function to the vesicular acetylcholine transporter in these same animals to potentially slow or stop the course of hippocampal dysfunction and memory loss. Our research will provide a deeper understanding of how chemical changes in the hippocampus contribute to the earliest cognitive symptoms of Alzheimer's disease, as well as how next generation therapies might target these changes to prevent disease onset and progression