University of South Florida

USF neuroscientist probes how different states of tau drive brain cell damage

Research by Laura Blair’s team seeking to untangle tau may lead to targeted treatments for Alzheimer’s, Parkinson’s and other neurodegenerative diseases

Both of USF Health neuroscientist Laura Blair’s grandmothers died from ALS, a debilitating neurodenerative disease that progressively weakens muscles and leads to paralysis.

Laura Blair, PhD, assistant professor in the Department of Molecular Medicine, at her laboratory in the USF Health Byrd Alzheimer’s Institute

“Seeing that firsthand really put in my heart to do everything I could to help people suffering from these devastating neurodegenerative diseases,” said Blair, PhD, an assistant professor in the Morsani College of Medicine’s Department of Molecular Medicine.

As an USF undergraduate student conducting research in chemist Bill Baker’s laboratory, she had the chance to work at the USF Health Byrd Alzheimer’s Institute with Chad Dickey, PhD, an accomplished and creative NIH-funded neuroscientist who was the first to find that proteins involved in learning and memory were selectively impaired in a mouse model of Alzheimer’s disease.

Blair jumped at the opportunity.  Dr. Dickey’s National Institutes of Health (NIH) work was focusing on defects in the removal of damaged proteins from cells, with promising studies of the key role “chaperone proteins” play in regulating brain cell function in Alzheimer’s disease and other neurodegenerative disorders.

“I was excited to be part of the translational work he was doing – seeking to understand how the cell’s natural defense, these chaperone proteins, might be harnessed to regulate (abnormal) misfolding proteins in order to help fix or prevent neurodegenerative disease,” Dr. Blair said.

That was nine years ago.

Dr. Blair pulls up microscopic images of stained neurons with doctoral student Lindsey Shelton, right. The stain is used to determine if treatments administered to mice —  for instance, overexpressing cochaperone protein Aha1 or human enzyme CyP40 — change how toxic tau becomes to nerve cells.  

COPH sound-icon-png Dr. Laura Blair describes the focus of her laboratory’s research.

Carrying on a scientific legacy

Since then, Dr. Blair received her doctorate in medical sciences at USF in 2014 (she also earned bachelor’s and master’s degrees here) and continued to work in Dr. Dickey’s laboratory as a postdoctoral fellow.  When Dr. Dickey passed away last year at the age 40 following a courageous battle with cancer, Dr. Blair and colleague John Koren, PhD, assumed the leadership of Dickey’s team with heavy hearts. But they push forward with their mentor’s same dedication to seeking answers and sense of urgency to “publish, publish, publish.”

“Chad was always larger than life and one of the biggest influences in my life, so losing him has been surreal,” said Blair, who keeps Dr. Dickey’s nameplate on the office she now occupies. “It’s hard, but we will continue the work he started and carry on his scientific legacy.”

“He was a tremendous mentor who taught all of us how to think about a problem and ways to come up with solutions.” And she said, smiling at the memory of Dr. Dickey’s unrelenting drive to find solutions, “he taught us there’s no sense in waiting until tomorrow for an experiment that could have been started yesterday.”

Dr. Blair with Jeremy Baker, doctoral candidate in the Department of Molecular Medicine who was the lead author for a recent PLOS Biology paper reporting that a human enzyme can reduce neurotoxic amyloids in a mouse model of dementia.

Dr. Blair’s laboratory studies how chaperone proteins drive different states of the tau protein associated with Alzheimer’s disease and more than a dozen other tauopathies, including Parkinson’s disease and traumatic brain injury.  Just as their name suggests, “chaperone” proteins escort other proteins in the cell to the places they need to be, ensure these proteins do not interact with others that could be bad influences, and see to it that proteins degrade, “or are put to bed, so to speak,” when the time is right, Dr. Blair said. Under normal circumstances, chaperone proteins help ensure tau proteins are properly folded to maintain the healthy structure of nerve cells.

Pursuing how chaperones drive different states of tau

In particular, the USF researchers explore how various chaperone proteins interact, for better or worse, with various forms of tau – ranging from soluble tau protein that can spread from one brain cell to another to the aggregated, misfolded species of tau tangles inside brain cells.  (Sticky plaques of B-amyloid protein and toxic tangles of tau protein both accumulate in patients with Alzheimer’s disease, but recent studies suggest that tau deposits may be more closely linked to the actual death of neurons leading to memory loss and dementia.)

“If we can understand which states of tau are worse in terms of driving neurotoxicity,” Dr. Blair said, “maybe we can begin to shift tau into a better state so we can help delay disease progression, if not stop it in its tracks.”

COPH sound-icon-png Dr. Blair comments on differences in Alzheimer’s disease.


Dr. Blair and colleague John Koren, PhD, assistant professor (far left), co-manage a research team focusing on how chaperone proteins drive different states of the tau protein associated with Alzheimer’s disease and more than a dozen other tauopathies.


.With a support of a new five-year, $1.5-million R01 grant from the National Institute on Aging, Dr. Blair, along with co-principal investigators Paula Bickford, PhD, of the USF Center of Excellence for Aging and Brain Repair, and Vladimir Urvesky of the Department of Molecular Medicine, is looking at a family of energy-independent, small heat shock proteins known to prevent harmful tau aggregation.  In an earlier paper published several years ago in the Journal of Neuroscience, Drs. Blair, Dickey and colleagues reported that high levels of one of these chaperone proteins, Hsp27, reduced tau accumulation in neurons and rescued learning and memory in a mouse model for Alzheimer’s disease.

Dr. Blair is also principal investigator of a second, five-year $1.36-million grant from the National Institute of Mental Health (the continuation of a grant originally awarded to Dr. Dickey) to develop a treatment blocking the effect of a stress-related protein genetically linked to depression, anxiety and other behaviors associated with post-traumatic stress disorder (PTSD). The grant builds upon earlier USF research, showing that as levels of this stress-related protein, known as FKBP51, increase in the brain with age it partners with chaperone protein Hsp90 to make tau more deadly to brain cells involved in memory formation. Using a new mouse model genetically engineered to overexpress FKBP51 and exhibit symptoms like those seen in humans with PTSD, Dr. Blair’s team will test various treatments on mice exposed to early-life environmental stresses.

Dr. Blair and Shelton, lead author of a USF-led paper published this September in Proceedings of the National Academy of Sciences demonstrating that Hsp90 cochaperone Aha1 boosted production of toxic tau aggregates in a mouse model of neurodegenerative disease. 

The ultimate goal of all this tau regulation research is to discover and commercialize targeted treatments that work, whether that’s drugs that inhibit or activate chaperone proteins, or gene therapies, or a combination. Currently no FDA-approved medications for Alzheimer’s disease specifically target beta amyloid or tau; they only help improve symptoms for some patients for a limited time.

A single-bullet therapeutic approach to a disease like Alzheimer’s that affects diffuse areas of the brain is unlikely, Dr. Blair said. “The multi-treatment option is probably going to be the most effective, but it’s difficult to address that until we have individual treatments moving forward.”

“Working toward treatments to help slow and prevent these devastating neurodegenerative diseases is what keeps our laboratory so motivated and determined.”

COPH sound-icon-png On working in a building that bridges research and clinical care


Slides, containing stained nerve cells from mouse brain tissue, are used by the researchers to evaluate neuronal health following various treatments.

Identifying potential treatments for neurodegenerative diseases

Building on Dr. Dickey’s work with chaperone proteins, the USF researchers continue to make significant progress in identifying potential targets to help slow or prevent neurodegenerative disease progression.

The team recently identified cochaperone protein Aha1, which binds to and stimulates the activity of heat shock protein Hsp90, as one promising therapeutic target.  Hsp90 regulates the folding, degradation and accumulation of tau. In a study published this September in  Proceedings of the National Academy of Sciences, the researchers demonstrated that Hsp90 cochaperone Aha1 boosted production of toxic tau aggregates in a mouse model of neurodegenerative disease and led to neuron loss and memory impairment.

The researchers also found that inhibiting Aha1 prevented the dramatic accumulation of tau in cultured cells. “We think Aha1 inhibitors offer promise for effects similar to Hsp90 inhibitors with less side effects,” Dr. Blair said.

Dr. Blair and Shelton work at an automated stereotactic injector station. The equipment helps the researchers determine the effects of gene therapy in the brain.

This June, in the journal PLoS Biology, Dr. Blair (principal investigator), Jeremy Baker (lead author) and colleagues reported for the first time that a naturally-occurring human enzyme – called cyclophilin 40 or CyP40 – could break apart clumps of tau in a mouse model of dementia. The USF led study found that CyP40 reduced the amount of aggregated tau, converting it into a more soluble and less toxic form of amyloid. In a mouse model of an Alzheimer’s-like disease, experimental expression of CyP40 preserved brain neurons and rescued cognitive deficits. The same enzyme also disaggregated alpha-synuclein, an aggregate associated with Parkinson’s disease.

Exactly how CyP40 can untangle clumps of tau and alpha-synuclein is not yet clear, but, Blair said “our finding suggests that CyP40, or one of the more than 40 other proteins with similar activity, may have a role to play in treating neurodegenerative diseases.”

Dr. Blair points to the hippocampus on the map of a mouse brain. An area critical for learning and memory, the hippocampus is especially vulnerable to damage at early stages of Alzheimer’s disease.

COPH sound-icon-png What Dr. Blair hopes she can impart to students as a mentor


Some things you might not know about Dr. Blair:

  • Blair and her husband Tom belong to a local swing dancing community, where they enjoy dancing the Lindy Hop and Balboa to ‘40s jazz.
  • Blair is a mother to 7-year-old Oliver, and a stepmother to 17-year-old Laney, who is a high school senior. They also have two dogs, a Shih Tzu named Oreo and a Shih Tzu-Yorkshire terrier mix named Pumpkin.
  • Participating in the Great American Teach-in two years ago, Dr. Blair spoke to her son’s kindergarten class about her career as a neuroscientist, including working on brain teaser puzzles and discussing a video of a preclinical neurobehavioral test with the young students. But, she said, the kids were particularly impressed with the squishy plastic “stress-reliever brains” she brought along.

Research associate Leo Breydo loads protein into a gel.

Cultured cells are harvested for analysis.

-Photos by Sandra C. Roa and Eric Younghans, University Communications and Marketing

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