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2019 Alzheimer's Association Research Fellowship to Promote Diversity (AARF-D)

Exploring Aha1 and Tau Relationship

Could targeting the biology of how a protein folds help prevent tau tangles in Alzheimer’s?

Marangelie Criado-Marrero, Ph.D., M.B.A
University of South Florida
Tampa, FL - United States


The brain cell’s nutrient and energy transport system is organized in parallel strands like railroad tracks. These tracks allow nutrients to travel across the cell, delivering key materials to the cells, providing them with energy and keeping them healthy. The tau protein helps keep these tracks straight. However, in Alzheimer’s and other brain diseases like frontotemporal dementia and Pick’s disease the shape of tau protein becomes modified or “misfolded” and this could contribute to tau tangles (a hallmark of  these diseases) and subsequent nerve cell damage.
Previous research by Dr. Marangelie Criado-Marrero has found a protein called Aha1 accumulates near tau tangles in mouse models of Alzheimer’s. Aha1 normally helps guide (or “chaperone”) protein folding inside cells, but Dr. Criado-Marrero found that Aha1 in combination with another protein may contribute to tau misfolding and accumulation in the brains of the mice.

Research Plan

In the current study, Dr. Criado-Marrero and colleagues will test whether reducing Aha1 can slow tau accumulation and memory loss in genetically-engineered Alzheimer’s-like mice. They will also test whether increasing Aha1 levels in the mice worsens tau tangles (to help confirm Aha1’s role). In both scenarios, the researchers will analyze the amount of tau and nerve cells in the mouse brains. They will also measure how well the mice perform on learning and memory tests to see if changing Aha1 levels has any impact on cognitive symptoms associated with Alzheimer’s.
In the last part of the study, Dr. Criado-Marrero’s team will examine how other “chaperone” proteins like Aha1 may contribute to accumulation of abnormal tau. The researchers will mix tau with different proteins that normally help proteins fold. Using high-powered microscopes, the researchers will identify which additional proteins work together with Aha1 to form tau tangles, and which proteins may help maintain healthy forms of tau.


The results of this study could provide insights into how tau may become modified during Alzheimer’s. It may also reveal how several “chaperone” proteins work together to maintain proper tau folding. Aha1 may also represent a new, therapeutic target for Alzheimer’s.

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