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2025 Oxford-Harrington Rare Disease Scholar Award
Neuroscience
An Aha(1) Disrupter for Tauopathies
2024 Douglas Scholar, Harrington Brain Health Medicines Center
Researchers know the rewarding feeling of an “aha moment,” when a significant discovery is made. Such a moment is usually figurative, but in the case of Dr. Blair and a collaborative team searching for new therapies to treat Alzheimer’s disease, it was also literal.
Dr. Blair, lead investigator, and co-principal investigator Brian Blagg, PhD, professor of chemistry and biochemistry at the University of Notre Dame, have demonstrated that the activator of Hsp90 ATPase activity (Aha1) promotes the assembly of tau fibrils that contribute to Alzheimer’s disease.
They have found that levels of Aha1 correlate with tau pathology in Alzheimer’s disease, while other groups have shown that Aha1 interacts directly with tau in neurons and higher Aha1 is associated with worsened neuronal health—all of which supports targeting Aha1 as a therapeutic approach for Alzheimer’s. The team has developed Aha1/Hsp90 disruptors that reduce tau aggregation in recombinant and cellular models, and is seeking to characterize the in-vivo properties of their lead compound to understand its binding to Aha1 and prepare for additional optimization.
“We hypothesized that breaking up the interactions between Aha1 and Hsp90, these proteins that together promote the aggregation of tau, will slow down that accumulation and be beneficial for patients that have Alzheimer's disease and other related tauopathies,” Dr. Blair said.
She added that there are about 25 other neurodegenerative diseases categorized as tauopathies where tau aggregation occurs and is a part of the damage in the brain.
“We think that there is potential for many individuals to benefit from a tau-targeted therapy such as this,” Dr. Blair said.