2024 Alzheimer's Association Research Grant (AARG)

Endosomal Control of Protein Synthesis in Alzheimer’s Disease

How do proteins and genetic material important for Alzheimer’s move through nerve cells?

Jean-Michel Cioni, Ph.D.
Università Vita-Salute San Raffaele
Milan, Italy

Background

Brain cells take up and transport nutrients, small molecules, and proteins through a process called “endocytosis” where material is packaged into “endosomes” which carry this material throughout the cell. Research by Dr. Jean-Michel Cioni and others has shown endosomes also play a role in making proteins inside cells. Researchers have found RNA, the genetic material that contains instructions for making proteins, and cellular machinery responsible for making proteins on endosomes. In Alzheimer’s, endocytosis is disrupted and endosomes can accumulate, but it is not clear how this might affect protein production inside cells.

Research Plan

In the current study, Dr. Cioni and team will study how RNA and proteins important for Alzheimer’s move through nerve cells via endosomes, and how this changes during Alzheimer’s. First, the research team will use specialized microscopes to view the locations of endosomes inside mouse nerve cells growing in laboratory dishes. They will measure levels of relevant RNA molecules and monitor endosome movement through the cells. They will also use genetic engineering to create nerve cells that contain endosomes similar to those seen in Alzheimer’s. The researchers will determine if this changes how endosomes containing RNA relevant to Alzheimer’s move through the cells.

Next, Dr. Cioni and colleagues will analyze specific pieces of RNA that are required to maintain nerve cell health. These important RNAs must navigate to precise locations within nerve cells to perform their function. The research team will determine if Alzheimer’s-related changes to nerve cells has any impact on endosomes’ ability to shuttle these protective RNAs to their normal location.

In a final step, the researchers will analyze how beta-amyloid, a hallmark protein often seen in the nerve cells of people with Alzheimer’s, affects the movement of endosomes containing RNA or proteins important to Alzheimer’s. The researchers will expose mouse nerve cells growing in laboratory dishes to beta-amyloid proteins, and then use specialty microscopes to monitor any changes in endosome movement.

Impact

This study will provide a detailed description of the cellular location and dynamics of RNA and proteins that are central to Alzheimer’s. Findings from this study could provide a deeper understanding of how protein production in nerve cells changes during Alzheimer’s, and how this might be mitigated.