Astrocytic Calcineurin and Connexin43 Gap Junctions in Alzheimer's Disease

As the sixth leading cause of death that affects over 5.2 million people, Alzheimer’s disease (AD) is becoming a health crisis. Because previous clinical trials have been disappointing, it is critical that new and alternative molecular targets be explored. The proposed project will test the overarching hypothesis that calcineurin (CN) and connexin43 (Cx43) interactions disrupt gap junction (GJ) coupling in astrocytes during the progression of AD leading to detrimental changes in neurologic function. This project will use a multi-disciplinary approach to investigate the hypothesis using human hippocampal specimens, APP/PS1 transgenic mice, and rat primary astrocyte cultures. Additionally, this project will use a variety of cutting-edge techniques, including fluorescence resonance energy transfer (FRET), adeno-associated virus (AAV) - mediated gene delivery, and slice electrophysiology. The overarching hypothesis will be examined through three independent specific aims which are as follows: to test the hypothesis that CN interacts with Cx43 during the progression of AD; to test the hypothesis that beta amyloid (Aâ) disrupts GJ coupling in a CN-dependent manner; to test the hypothesis that CN/Cx43 interactions disrupt GJ coupling and neurologic function in a mouse model of AD. This project not only provides superior training in neuroscience research, but also will provide extremely valuable information into a potential new therapeutic target for AD.