Alzheimer’s disease (AD) is the most common form of dementia with no cure and a 100% fatality rate. The disease starts in the brain many years before the first symptoms occur. Two critical factors in the progression of AD are the vessels in the brain, termed neurovasculature, and the immune system. While the neurovasculature normally forms a tight barrier between the immune system and the brain, this barrier breaks in AD, enabling immune cells to enter the brain. Studies in mice and humans show that this barrier breakdown and AD progression are accelerated by psychosocial stress. In this project, we aim to understand how stress fuels AD and to identify innovative therapeutic targets to stop this process. Over the last two years, we have generated, validated, and implemented tools to study the effects of stress on AD. We have made significant progress in defining the impact of social stress on social and reward deficits observed in AD. In work proposed here, we will manipulate brain centers under relaxed conditions and inhibit them under stressed conditions to understand their individual contributions to AD. We will apply cutting-edge technology, including chemical and light stimulation of specific neurons, to identify novel therapies to stop the detrimental effect of stress on AD and to potentially even slow down or reverse AD progression altogether. We envision that highly specific manipulation of distinct brain areas may offer new hope for AD patients and their families.
