Circuit vulnerability of the lateral and medial entorhinal cortices in tauopathy models of Alzheimer's disease

Project Summary Alzheimer’s disease (AD) currently affects ~6.7 million individuals in the U.S. alone and is expected to grow to 13 million by the year 2050. A major component of its devastation is the progressive loss of the patient’s ability to form memories. Treatments for rescuing memory function in AD patients do not exist, due in part to insufficient research performed to characterize the activity of memory-supporting neural circuits compromised by the disease. The effort to develop memory-restorative therapeutics that intervene in neural circuits requires vulnerable neuronal subtypes impacted during pathophysiological progression, and how they relate to memory performance. Neurons in the entorhinal cortex (EC) act as a gateway for sensory inputs feeding into the hippocampus. This EC-hippocampus circuit is critical for memory formation and retrieval. Despite its significance to AD pathophysiology, it remains unclear which circuit components are vulnerable in the EC of AD patients or animal models. Our laboratory’s pioneering previous research has developed exciting preliminary results that suggest a path forward. Our overall hypothesis is that circuit vulnerability of the EC, including the lateral entorhinal cortex and medial entorhinal cortex, to tauopathy causes associative memory impairment in AD. We will use two Tau mouse models to identify EC cell types vulnerable to tauopathy. The project is expected to yield advances toward the development of therapeutics to mitigate associative memory functions impaired in AD.