Chad Dickey, Ph.D.
Assistant Professor of Molecular Medicine, University of South Florida
Recipient of a 2006 New Investigator Research Grant
In his own words, investigator Dr. Chad Dickey, describes his research and what receiving Association funding has meant to his career.
With funding provided by the Alzheimer's Association, we implemented a novel screening technique that not only identifies drugs that may be new treatments for Alzheimer's disease, but also sheds light on new mechanisms for identifying better drug targets in the future. In particular, we have focused on using chemicals to promote recycling and clearance of the tau protein, which accumulates in abnormal amounts in the brains of those with Alzheimer's.
"The faith that the Alzheimer's Association places in junior investigators by providing them with a possible funding source has been critical for progress in the field. By providing an influx of new ideas and scientists in the Alzheimer's community, therapies that likely would never have been considered may get to the clinic for Alzheimer's patients."
Without support from the Alzheimer's Association, the following work may never have been done. Moreover, it is quite possible that I might have left science or changed fields simply due to the extremely challenging funding environment that currently exists in science as a result of the economic crisis we face in the United States.
Recycling and clearance of tau
We found that over-expression of mutant human tau impairs the turnover of otherwise normal tau in the mouse brain. We also found that young mice are capable of clearing tau while older animals are not. In addition, we found that heat shock proteins, which are essential for preserving tau in the brain, were present in low levels in young mice relative to old mice. This could indicate that heat shock proteins are contributing to tau pathology.
Using drugs from our screen that inhibit heat shock proteins, we found that if other proteins are accumulating in the brain at the same time as tau, there might be a cellular 'log-jam' at the protein clearance system, leading to aggregation of tau. Other drugs identified from our screen were then tested in mice.
Methylene blue and memory
Twenty-four hours after injection we found that methylene blue (MB) and its derivative azure C (AC) could effectively lower tau levels in the brains of mice. We are currently analyzing data from a long-term study with MB that show that memory function is improved in mice treated with MB compared with untreated mice. We also saw a reduction in tau levels in mice treated with MB.
Interestingly, MB was recently proposed to inhibit tau protein aggregation, and this function, coupled with its low toxicity profile, propelled it into clinical trials for Alzheimer's, where it has been met with guarded enthusiasm.
Through our screen and subsequent work, we have identified that MB reduces tau levels by inhibiting a heat shock protein called Hsp70. In collaboration with the Gestwicki Laboratory at the University of Michigan, we have found that Hsp70 activators significantly increased tau levels. Collectively, these data demonstrated that the breakdown of tau is rapidly facilitated when Hsp70 is inhibited by MB. It also suggests that Hsp70 activity prevents the degradation of tau, underscoring its value as a therapeutic target for Alzheimer's.
Thus, while the use of MB in the clinic is entering Phase III clinical trials for the treatment of Alzheimer's disease, its role as an aggregation inhibitor may be superfluous to its more important function of inhibiting Hsp70 activity. By identifying the primary target of MB as Hsp70, the development of more potent Hsp70 inhibitors with superior ability to cross the blood-brain barrier can begin. This discovery could prove to be a critical cornerstone for other neurodegenerative diseases and make Hsp70 inhibition a viable therapeutic approach. By identifying Hsp70 as a major contributor to tau degradation, we have a more complete understanding of how Alzheimer's disease starts.
Moving research forward
The faith that the Alzheimer's Association places in junior investigators by providing them with a possible funding source has been critical for progress in the field. By providing an influx of new ideas and scientists in the Alzheimer's community, therapies that likely would never have been considered may get to the clinic for Alzheimer's patients.
As the recipient of a New Investigator Research Grant (NIRG), I can personally attest that without the grant, I would not have had the same success. To be quite frank, I likely would have changed to the cancer biology field had it not been for the NIRG, simply because the funds available for cancer research are so much greater than for Alzheimer's. Providing these grants to new investigators at a stage when we are just establishing ourselves in the field gives us just enough resources to persevere in our work on Alzheimer's. These funds provide the foundation for future clinical successes in Alzheimer's, as evidenced, in small part, by the progress we have made over the past three years toward our ultimate goal: to identify drugs that modify the biological processes leading to the accumulation of tau and perhaps improve the quality of life for millions of people living with Alzheimer's.”
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