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2022 Alzheimer's Association Research Grant (AARG)

Engineered Decoy Viral Inhibitors (DEVi) to Prevent Tau Spread by LRP1

Can a virus-associated protein help prevent the development of tau tangles, a hallmark of Alzheimer’s?

Gaya Amarasinghe, Ph.D.
Washington University in St.Louis
St. Louis, MO - United States



Background

Tau protein helps maintain the structure of brain cells. In Alzheimer’s and other brain diseases, the shape of tau becomes modified, or “misfolded”, a change that may contribute to tau tangles (a hallmark of these diseases) and subsequent nerve cell damage.

Recent studies suggest that the protein LRP1 (low-density lipoprotein receptor-related protein 1) may be important for the removal of tau from the brain. Loss of LRP1 function has been shown in both Alzheimer’s-like mice and in the brain tissue of individuals who had Alzheimer’s, but the underlying biology that drive this change are not understood.

Research Plan

In initial research with brain cells grown in a laboratory dish, Dr. Gaya Amarasinghe and colleagues found that tau can bind to the protein, LRP1, and reduce LRP1 activity. They also found that a protein associated with some viruses, called Rift Valley fever virus glycoprotein N (RVFV Gn) may be able to prevent the interaction of tau and LRP1. The researcher team believes that the RVFV Gn can prevent this interaction by acting as a “decoy” and binding to the same site on LRP1 as tau, and will aim to better understand the underlying biology.     

Dr. Amarasinghe and team will work to verify and expand their initial research on tau and LRP1. They will engineer cells in a laboratory dish that lack LRP1, and examine how the absence of this protein impacts the buildup of the tau protein in the cells. Next, using another group of laboratory cells with LRP1, they will aim to understand how the RVFV Gn may impact the interaction of tau and LRP1.  Lastly, the investigators will engineer new “decoy” proteins based on the characteristics of RVFV Gn, and compare how well the different proteins block tau accumulation in laboratory cells.

Impact

Results from this study could shed new light on how tau and LRP1 interact in Alzheimer’s. They could also identify a novel viral therapy for targeting tau proteins.

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