Aging changes the adult brain both structurally and functionally. Something about these changes promotes cognitive decline and increases the risk of Alzheimer?s disease, a neurodegenerative disease that affects millions of Americans and is the leading cause of dementia among adults. I propose to carry out longitudinal electrophysiology and behavioral studies to understand how age-related changes in individual neurons and their circuits contribute to cognitive impairments in mouse models of aging and Alzheimer?s disease. I plan to take advantage of a novel biotechnology, mesh electronics, that will overcome many previous challenges preventing the study of aging processes of single neurons and their circuits. I will use this technology combined with behavioral tasks in virtual reality to understand how neurons and their circuits within the hippocampus and entorhinal cortex change with normal aging and lead to cognitive decline. Then I will perform similar studies to understand how spatial memory and learning deficits arise in a model of early aging in Alzheimer?s disease that expresses pathological tau, with the goal of determining if either soluble or aggregated tau leads to neuronal dysfunction and spatial memory impairment or if they arise coincidentally. These data will be extremely valuable for the medical community as aggregated tau is currently the target of several ongoing clinical trials. These experiments will also establish mesh electronics as a useful tool for the study of normal and pathological aging that could be extended to understand the onset of cognitive decline in many other model systems.
These experiments will provide insight into processes that contribute to cognitive decline with aging and Alzheimer?s disease. I will look at how neurons and their circuits change with age and try to determine which features are harmful and which features are coincidental. These data will help understand what form of the protein tau, a pathological hallmark of Alzheimer?s disease, should be targeted by clinical trials to treat cognitive decline in Alzheimer?s disease.
