Using Polylox DNA barcodes to lineage trace adult neural stem cells in Alzheimers Disease

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PROJECT SUMMARY New neurons are produced from dedicated neural stem cells throughout the lifespan of humans and animals. The level of adult neurogenesis in the hippocampus declines with age and is drastically affected by neurodegenerative disorders such as Alzheimer's disease (AD). Adult hippocampal neurogenesis is implicated in cognitive function, mood, and stress response and its augmentation is considered as a potential strategy for mitigating the effects of AD. Accurate lineage tracing could help in understanding how aging and AD alter the division dynamics of adult neural stem cells. However, current tools used to lineage trace the division of adult neural stem cells, and their subsequent maturation in neurons, are limited in their scope. This has contributed to conflicting models of adult neurogenesis, hindering progress in understanding the true potential of adult neurogenesis as a means of reducing the effects of AD. Our proposal aims to move the field forward by using a new DNA/RNA barcoding approach to study clonality and lineage of adult neural stem cells in a mouse AD model. This research plan will match single- cell endogenous barcoding and transcriptional profiling of the hippocampal stem cells and their progeny. This will uncover the life cycle of neural stem cells in the normal aging and AD-affected brain. A particular emphasis of the project is the possibility of selective expansion or deletion of subclasses of stem cells during AD progression, thereby potentially defining the properties of new hippocampal neurons born during the development of AD. Our findings could be later used to design new therapeutic strategies to combat the loss of neurons that occurs in AD.