Development of novel genomic approaches for profiling cellular temporal-spatial dynamics of neurogenesis in Aging and Alzheimer's disease

PROJECT SUMMARY
Adult neurogenesis is emerging as an important player in maintaining brain homeostasis and normal functions.
The dysfunctions of neurogenesis have been associated with aging and neurological disorders, including
Alzheimer’s disease (AD). The ability to systematically map the molecular dynamics of neurogenesis at single-
cell resolution could serve as a foundation for a systematic effort to better understand the molecular events that
give rise to abnormal cell states in aging and diseases. While the rapid advances in single-cell genomics are
creating unprecedented opportunities to explore molecular heterogeneity in mammalian brains, nearly all such
methods are restricted to low throughput and fail to recover the heterogeneity and dynamics of the profoundly
rare cell states in adult neurogenesis (e.g., less than 0.1% of the cell population in the brain). Herein, we propose
to develop novel methodologies that enable a comprehensive view of temporal-spatial dynamics of neurogenesis
during aging and Alzheimer's disease (AD) in both human and mouse brains. Specifically, we will first develop a
novel high-throughput, low-cost single-cell genomics approach, sciNext1000, to profile the molecular
heterogeneity of four million cells from post-mortem human hippocampal samples. This approach will be powerful
because we can not only quantitatively characterize the frequency of human adult hippocampal neurogenesis at
single-cell resolution, but also identify the transcriptome features associated with impaired neurogenesis in aging
and AD at isoform resolution. In addition, we will develop another novel single-cell genomic technique, sci-Div-
seq, to enhance the detection of newborn neurons, and identify the cellular differentiation trajectories and
associated transcriptomic features of adult neurogenesis in young and aged mouse brains. The resulting dataset
will advance our understanding of gene regulation in neurogenesis across different neural lineages and
constitute a significant step towards a comprehensive characterization of the molecular mechanism underlying
neurogenesis impairment in aging. In addition to the internal molecular programs, the neurogenesis process is
controlled by aspects of environmental signals from the neural stem niche. We will apply a high-throughput
spatial transcriptomic strategy to identify the cellular interactions and local microenvironment involved in adult
neurogenesis in both human and mouse brains. These multi-pronged approaches will open a new paradigm for
understanding the global molecular programs and environmental regulation of adult neurogenesis, thereby
informing potential therapeutic targets to restore cell population homeostasis in aging and brain disorders.

Grant Number: 5R01AG076932-04
NIH Institute/Center: NIH
Principal Investigator: Junyue Cao