Grant: Project Grant

Alzheimer's disease is the primary form of dementia in old age and rates are increasing due to longer human lifespan and the aging population of baby boomers. It is estimated that prevalence will quadruple between 2006 and 2050, at which point 1% of the worldwide population will have the disease. Despite these bleak figures, it is important to note that patients typically only live with the severest form of Alzheimer's for 1-2 years. Thus, treatments that can delay disease progression have tremendous potential to reduce the burden of Alzheimer's disease. Here, we will identify exactly which brain cells and circuits are initially most vulnerable to the tau pathology that is observed in aging and Alzheimer's disease. Tau is a toxic protein that is first observed in the memory centers of the brain, before spreading and causing irreversible damage. More specifically, the neurons that first harbor tau also connect with another region that produces newborn neurons throughout life. These newborn neurons have an enhanced ability to integrate into neural circuits, suggesting they may be better at forming connections in disease states. However, no one has ever examined whether they less vulnerable to tau, or more capable at repairing circuits that are damaged by tau. Here we will therefore mimic the human pattern of tau pathology in mice, and examine whether new vs. old neurons are more likely to be damaged. We will then use various therapeutic strategies to enhance new cell growth, with the goal of repairing the damaged circuits. Whereas we currently know, at a general level, which brain regions are sensitive to tau pathology and Alzheimer's disease, these experiments will reveal the precise subpopulations of neurons that are vulnerable and capable of being exploited to delay the progress of disease.