Advanced Imaging of the Spatial Organization of Brain Cells in Alzheimer’s Disease

Project Summary

Aim 1: Develop a highly multiplexed tissue imaging method to detect mRNA isoforms in their native tissue context with single-cell and spatial resolution. Aim 2: Build a map of the spatial organization of different cell types in brain tissues with gene-level and isoform-level resolution. Aim 3: Map the propagation of tau into different cell types and brain regions from early to late stages of disease using spatial transcriptomics. The purpose of this aim is to understand cell type vulnerability to tau propagation in the brain throughout disease progression using spatial transcriptomics. 

The brain is characterized by a complex transcriptome, with higher levels of isoforms than other tissues. Isoforms are important for neuronal function and their dysregulation is associated with neurological diseases. Methods that can comprehensively map isoforms in their native tissue context in single-cells and with spatial resolution are limited. I will develop a method that fills this gap and use it to map the spatial organization of cell types in the brain. I will use this method to understand which cell types and cellular environments are vulnerable to tau propagation in Alzheimer’s. A new imaging method for highly multiplexed isoform detection in brain tissues will be developed. This method opens the possibility to detect biologically important isoforms with spatial resolution for many applications including understanding the spatial organization of the brain, identifying new cell types, and disease studies. This method will be used to map the spatial organization of different cell types in the brain. This method will then be used to understand neuronal cell type vulnerability to tau propagation in various brain regions, providing important insights on AD pathophysiology.