Alzheimer’s Association International Research Grant Program: Alzheimer’s Association Research Fellowship (AARF)
Understanding the neural basis of Alzheimer’s disease (AD) is critical for early detection and improving quality of life. Among the earliest signs of preclinical AD are navigation impairments and the presence of abnormal Tau (aTau) proteins in the entorhinal cortex (EC), a brain region that represents space and movement. The EC is the main input node to the hippocampus, a region critical for navigation and episodic memory. As AD progresses, EC aTau spreads to the nearby subiculum, the main output node for the hippocampus. While aTau in EC disrupts spatially modulated cells and impairs spatial memory, the effects of aTau on spatial coding in the subiculum are unknown. Furthermore, it is not known how navigation impairments in preclinical AD progress to the episodic memory loss seen in clinical AD. We hypothesize that the spread of EC aTau to the subiculum will disrupt spatial coding and lead to wider memory deficits. To test this hypothesis, we will use a Cre-dependent viral approach to transfect mutant Tau in mice expressing Cre in EC layer III cells, to best approximate the aTau conditions of preclinical AD. We will track the spread of aTau as animals age to assess the rate and patterns of aTau propagation into the subiculum. To determine if EC aTau disrupts the encoding of experiences in the subiculum we will track the activity of subiculum neurons using in vivo calcium imaging as animals engage in spatial working memory (‘W-maze’) and episodic memory (contextual-fear conditioning) tasks. Finally, we will attempt to rescue any deficits in spatial coding in the subiculum through focal fornix stimulation, a proven method for recovering AD-related memory impairments. Understanding how aTau spreads from the EC into the subiculum and its impact on spatial/mnemonic processing in the brain is key to understanding the development of AD, and could ultimately lead to earlier detection and clinical interventions to better the lives of those at risk of, or living with, AD.