2021 Alzheimer's Association Research Fellowship (AARF)

Functional Characterization of new Alzheimer’s disease-Associated Proteins

What are the changes seen in Alzheimer’s in the compilation of proteins that protect and support brain cells?

David Li-Kroeger, Ph.D.
Baylor College of Medicine
Houston, TX - United States

Background

All cells in our body are surrounded by proteins that protect and support the cells during aging; these proteins are called extracellular matrix. Changes in the extracellular matrix of the brain are among the first biological changes in Alzheimer’s, but how these changes may contribute to neurodegeneration is not understood. 

With collaborators at Emory University, Dr. David Li-Kroeger and his team recently discovered a group of 29 brain extracellular matrix proteins that increase in association with the brain changes associated with Alzheimer’s. Preliminary studies identified one of these proteins, SMOC1, as potentially active in Alzheimer’s, though how changes in this protein may contribute to the brain changes associated with Alzheimer’s is not known.
 

Research Plan

Dr. Li-Kroeger and colleagues will study how changes in the extracellular matrix protein SMOC1 affects brain cell function and survival in Alzheimer’s using an advanced genetic model system of fruit flies. This model system has been used successfully in the past to identify specific genes responsible for numerous diseases, including brain diseases. Dr. Li-Kroeger’s research team previously showed that the fruit fly version of SMOC1, known as magu, is active in a subset of brain cells. 

Using this model, Dr. Li-Kroeger and his team will study the role of SMOC1/magu in the brain to understand whether it contributes to neurodegeneration and if so how it may be contributing. First, the researchers will determine if aging or Alzheimer’s-associated brain changes affect the activity of SMOC1/magu in genetically engineered Alzheimer’s-like flies and flies without any changes. The researchers will also study how changing the protein’s levels in specific cells may impact brain cell survival. 

In addition, Dr. Li-Kroeger and his colleagues will identify proteins that interact with SMOC1/magu and study how the composition the other proteins that it interacts with in the brains changes. The researchers will compare the data from their experiments with flies to analyses of human extracellular proteins.
 

Impact

Comparing findings from fruit flies with data from human brain samples may reveal insights into the role that the extracellular matrix may play in the biological underpinnings of Alzheimer’s. The results may identify new pathways important in Alzheimer’s as well as specific proteins that may serve as targets for future studies and drug development.