Visualizing How Alzheimer’s Mutations Alter Protein Localization in Human Brain Cells

This project will create a large-scale map of where Alzheimer’s-related proteins are located in human brain cells and determine how disease-causing mutations disrupt their normal organization.

Alzheimer’s disease is caused in part by proteins in the brain moving to the wrong locations due to mutations, which disrupt normal cell function. This project will use a precise genome editing method called Prime Editing to tag Alzheimer’s related proteins and introduce disease-causing mutations in human stem cells. These cells will be differentiated into neuronal and glial cell types, and advanced imaging combined with machine learning algorithms will map where each protein is normally located and how mutations alter their placement, providing a resource to guide future therapies.

This project combines next-generation prime editing with optical pooled screening, enabling thousands of genetic changes to be studied simultaneously in human brain cells rather than one mutation at a time. Unlike traditional approaches, this strategy allows direct visualization of endogenous proteins in living cells while linking each imaging phenotype to its precise genetic mutation at single-cell resolution. The resulting dataset will represent one of the first scalable atlases of Alzheimer’s related protein localization and mislocalization across diverse human neural cell types.

This study may reveal some of the earliest cellular changes that occur in Alzheimer’s disease before irreversible neuron loss develops. By identifying how disease-associated mutations disrupt protein organization in specific brain cell types, the work could help guide the development of therapies aimed at restoring normal protein function and cellular health. The open-access atlas generated by this project will also provide a valuable resource for researchers studying Alzheimer’s disease and related dementias worldwide.