Grant: DRA : Canada Graduate Research Scholarship - Doctoral Program (CGRS D)

Restoring neurons that are lost after brain injury or degeneration is a major unsolved challenge in neuroscience. In a pioneering strategy, another type of brain cell, a reactive astrocyte, can be directly converted into a neuron. Despite the incredible promise of astrocyte-to-neuron conversion (AtN) for brain repair, critical gaps remain in our understanding of downstream effects. Our preliminary data suggest that AtN does more than simply replace lost neurons. In a rat model of Alzheimer's disease (AD), AtN improved cognition and surprisingly reduced two key features of AD: amyloid plaques and neuroinflammation. Because astrocytes and neurons are part of a network of cells that communicate to regulate biological functions, I hypothesize that AtN promotes recovery in AD by changing this communication. I further propose that loss of reactive astrocytes, a source of inflammatory signals, reduces neuroinflammation, and that converted neurons become a source of signals that promote repair. I will use single-cell and spatial transcriptomics to measure gene expression in individual cells and to locate where these genes are expressed. First, I will use existing datasets from human AD patients and my dataset from AD rats to map the AD-disrupted communication networks with an emphasis on potential sex differences. I will then use gene delivery to induce AtN in both sexes of AD rats and comprehensively characterize the effects of AtN on all brain cells and the communication networks identified earlier. Finally, I will examine how these signals contribute to cognitive recovery by delivering inhibitory molecules, siRNAs, to reactive astrocytes (without AtN) or converted neurons (after AtN) that target specific communication signals. By clarifying the role of cell communication and sex differences in human AD and AtN-mediated recovery in a clinically relevant rat model, this work will enhance our ability to predict outcomes and guide the safe and effective clinical use of AtN.