2024 Alzheimer's Association Research Fellowship (AARF)

Spatial transcriptomic profiling of neuron-engulfing microglia

What signals determine whether a neuron lives or dies?

Lindsay Welikovitch, Ph.D.
Massachusetts General Hospital
Boston, MA - United States

Background

Alzheimer’s disease is associated with hallmark brain changes including the accumulation of the proteins, beta-amyloid and tau into abnormal plaques and tangles, respectively. Tau is a protein that helps maintain the structure of brain cells. In Alzheimer’s and other brain diseases, the shape of tau protein becomes modified or “misfolded,” a change that may contribute to tau tangles and subsequent brain cell damage. 

Microglia are the primary immune cells in the brain that serve as one of the first defenses against nerve cell damage. Microglia sense and help remove unwanted proteins or cells from the brain, in part through a process called phagocytosis, during which the microglial cells engulf (or “swallow”) the unwanted proteins or cells. Research has shown that microglia change in Alzheimer’s and may lose their ability to determine what needs to be cleared and what needs to stay. 

In this study, Dr. Lindsay Welikovich and colleagues plan to explore the types of signals that tell the microglia if they should engulf a nerve cell or leave it alone.

Research Plan

The research team will use genetically engineered Alzheimer’s-like mice that model brain changes related to tau accumulation. An advanced computational technique called spatial transcriptomics (the study of how gene activity is turned “on” and “off”) will be used to better understand different types of microglia, specifically, the microglia that engulf a nerve cell. Next, the research team will use the same technology to study different types of nerve cells, specifically, the nerve cells that are being engulfed by microglia. These comparisons will help researchers better understand the signals that are required for microglia to know which nerve cells to engulf and which nerve cells to leave alone. 

Impact

This study may contribute to our understanding of how different signaling in Alzheimer’s and other diseases with tau accumulation influence the behavior of microglia to engulf a nerve cell or preserve the nerve cell connections.