Developing a Comparative Single-Cell Spatial Transciptomic Atlas of Brain Aging in Non-Human and Humans

Project Summary Aging leads to an increased risk of neurodegenerative diseases such as Alzheimer's and Parkinson's that present significant public health challenges worldwide. Despite extensive research, the molecular mechanisms driving brain aging remain poorly understood, especially at the single-cell level within critical regions like the prefrontal cortex and hippocampus. Due to their close genetic and physiological similarities to humans, including comparable brain structure and aging processes, non-human primates (NHPs) like rhesus macaques are invaluable models for studying the intricacies of brain aging. This project aims to develop the first lifespan-matched, comparative single-cell spatial transcriptomic atlas of the prefrontal cortex and hippocampus in humans and rhesus macaques. Using the cutting-edge CosMx Spatial Molecular Imager (SMI), we will generate high-resolution, single-cell gene expression profiles across different life stages—young, adult, and aged—in both species. Our central hypothesis is that aging induces specific, identifiable spatial and cell-type-specific gene expression alterations conserved between humans and rhesus macaques, contributing to neurodegeneration. Under the guidance of expert mentors, the candidate will receive comprehensive training in NHP aging models, advanced spatial transcriptomics using the CosMx SMI platform, human neuropathology, data interpretation, and cross-species comparative analysis using integrative bioinformatics, leading to a deep understanding of the molecular mechanisms underlying brain aging. This project will fill a critical gap in our understanding of brain aging by providing the first lifespan-matched, comparative single-cell spatial transcriptomic atlases of key brain regions in humans and rhesus macaques. We anticipate that our findings will (i) advance our knowledge of age-associated molecular changes and (ii) identify conserved pathways contributing to neurodegeneration. Ultimately, this research has the potential to inform the development of therapeutic targets to mitigate neurodegenerative diseases, significantly impacting aging research and public health.