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2022 Alzheimer's Association Research Grant to Promote Diversity (AARG-D)

Role of Rho GTPases during amyloid-ß induced neuronal degeneration

Can changes in proteins linked to nerve cell structure promote Alzheimer’s-related nerve cell damage?

Mariano Bisbal, Ph.D>
Mercedes and Martin Ferreyra Institute for Medical Research
Cordoba, Argentina



Background

One of the changes observed in the brains of individuals with Alzheimer's is degeneration (breakdown) of synapses, the specialized connections between nerve cells that enable them to communicate with other nerve cells. Synapses often exist near "dendritic spines," which are small protrusions on the surface of dendrites (the "branches" of a nerve cell). Several studies have found that individuals with Alzheimer's have fewer dendritic spines than do healthy older individuals.

In order to protect dendritic spine health, nerve cells must maintain an internal "skeleton." Research suggests that this skeleton becomes abnormal when nerve cells are exposed to beta-amyloid, a protein fragment linked to Alzheimer’s-related brain cell degeneration and death. This type of exposure may explain the loss of dendritic spines in Alzheimer's. In more recent studies, Dr. Mariano Bisbal and colleagues found that when nerve cells grown in a laboratory dish were exposed to beta-amyloid oligomers (clusters of a few beta-amyloid molecules), they altered the activity of proteins called Rho GTPases. Rho GTPases help regulate the structure of nerve cell skeletons, and abnormal activity has been linked with the loss of dendritic spines. These findings suggest that beta-amyloid and Rho GTPases may interact to damage nerve cell health. 

Research Plan

Dr. Bisbal and team will conduct a larger study of Rho GTPases, beta-amyloid and nerve cell structure. They will use (1) mouse nerve cells grown in a laboratory dish, (2) nerve cells derived from induced Pluripotent Stem Cells (iPSCs, stem cells engineered from adult human cells that can be developed into any type of cell in the body), and (3) brain tissue from mice engineered to develop high levels of beta-amyloid. They will assess how beta-amyloid exposure over time changes the function of Rho GTPases in dendritic spines. Next, the investigators will study how beta-amyloid exposure impacts proteins that activate (turn on) Rho GTPases – and how these changes promote GTPase dysfunction. Lastly, Dr. Bisbal and colleagues will study how beta-amyloid-related GTPase activity may damage nerve cell skeletons and dendritic spines.  

Impact

Results from this project could shed new light on how beta-amyloid hinders nerve cell-to-nerve cell communication and promotes Alzheimer’s-related brain cell damage. They could also point to novel disease therapies that target Rho GTPases.

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