SHARE

 Please tell us about your educational background and research experiences.

I graduated from Medical School in 1970 having done an extra year of research in neurophysiology in 1967. In addition to routine internship, I then started to pursue neuropathological research topics, since my interest in brain disease really started in 1968, followed by doing a higher degree in Pathology (MD, 1977, "the pathogenesis of hydrocephalus").

 What first drew you to Alzheimer's disease (AD) research?

I had been working on the lesions of primates experimentally inoculated with "slow virus disease" kuru, Creutzfeldt-Jakob disease, and scrapie. As part of these studies involved looking for amyloid "kuru plaques," I needed to learn more about the plaques of Alzheimer's disease (AD). Initial attempts to purify kuru plaques were hampered by the low number of plaques, so I turned attention to purifying amyloid plaques from AD brain tissues.

"I'm hoping for a successful run of clinical trials which demonstrate the efficacy of early intervention for AD."

 Your most-cited original article in our analysis is the June 2001 Neuron paper, "Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice," (Cherny RA, et al., 30[3]: 665-76). Would you tell us a bit about this paper—your expectations going in, your findings, where this work has gone since this publication?

In 1994, Ashley Bush and Rudy Tanzi discovered discovered that Cu++ and Zn ++ bound to beta amyloid (Abeta). These studies arose from ideas that Ashley and I had about the roles of metal binding to amyloid precursor protein (APP). Subsequently, Mikis Xilinas drew our attention to clioquinol, a retired antibiotic drug with affinity for Zn ++.

It was Mikis' idea to test this drug in the AD transgenic model, which we did, with good results. Based on these data, we founded a company (Prana Biotechnology) to develop clioquinol as a lead compound. A derivative (PBT2) has now been taken through early clinical development, with encouraging results.

 In fact, a great deal of your work in our analysis deals with the roles of copper and zinc in Alzheimer's—what is it about these elements that make them so important?

Metal ions (such as Cu++, Zn++, Fe+++) are abundant and play important structural and functional roles in many diverse proteins. They are but one aspect of many factors that can influence the metabolism of proteins, and we were intrigued as to whether they could ever represent external environmental variables relevant to AD. Alas, no convincing evidence for this has so far emerged.

Nevertheless, as structural components which drive conformational changes in proteins/peptides with amyloidogenic propensities, they have remained high on our list of important drug targets. After all, our main goal is to find ways to therapeutically interfere with Abeta amyloidgenesis (including oligomerization), and thereby modify the rate at which AD develops. Delaying the onset of AD by only five years would dramatically alter the demographics of the illness.

 Your work ranked among the top 20 researchers in our earlier analysis of AD, which covered the 1992-2002 period, and now this one, which covers 2000-2010. Has the focus of your work changed in these periods, and if so, what factors influenced the changes?

"Delaying the onset of AD by only five years would dramatically alter the demographics of the illness."

We have a path which we have been following since the discovery of the Abeta peptides in plaques in 1984: slowly but surely we are moving from basic to applied research. Right now, we need to know much more on the natural history of AD, and when to intervene to delay onset.

 You are also involved in various research projects on imaging AD, most recently, the August 2010 Neurobiology of Aging paper, "Amyloid imaging results from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study of aging," (Rowe CC, et al., 31[8]: 1275-83, SI). Would you tell us about this aspect of your work?

To study the natural history of AD, we started the AIBL study in 2004, at a time when the first images of PET ligands binding to human brain amyloid were emerging. We have collaborated with Chris Rowe at the Austin Hospital and used this technology to help us identify the groups of prospective AD patients who we can enter in to clinical trials of delaying onset. This will be achieved by using biomarkers and neuroimaging in conjunction with disease-modifying therapies.

 Would you say we are in a better position today in terms of our knowledge of AD, the treatment options available, expected quality of life, etc., than we were in the 1990s? Why or why not?

We are undoubtedly in a better position today than 20 years ago, where now there are real therapeutic strategies poised to show efficacy. Outcomes of drug trials which have made it into Phase III have so far been disappointing, but most of these trials were destined to fail based on Phase II data or the drugs' mechanisms of action.

 Where do you hope to see this research go in the next decade?

I'm hoping for a successful run of clinical trials which demonstrate the efficacy of early intervention for AD. To do this will require much more attention to clinical trial design in the pre-symptomatic phase if AD. This is not a trivial exercise, but we now have the technology to do it.

Colin L. Masters, M.D.
Mental Health Research Institute
The University of Melbourne
Parkville, Victoria, Australia

---

COLIN MASTERS'S MOST CURRENT MOST-CITED PAPER IN ESSENTIAL SCIENCE INDICATORS:

Cherny RA, et al., "Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice," Neuron 30(3): 665-76, June 2001 with 519 cites. Source: Essential Science Indicators from Clarivate.

KEYWORDS: ALZHEIMER’S DISEASE, NEUROPATHOLOGY, KURU, CREUTZFELDT-JAKOB, SCRAPIE, AMYLOID-BETA, AMYLOID PRECURSOR PROTEIN, COPPER, ZINC, IRON, CLIOQUINOL, PBT2, PROTEIN METABOLISM, OLIGOMERIZATION, DELAYING ONSET, NATURAL HISTORY, AIBL STUDY, BIOMARKERS, NEUROIMAGING, PET LIGANDS, CLINICAL TRIALS.

EMAIL   |   BACK TO TOP

---

• Special Topics
• Alzheimer's Disease
• Colin Masters Interview - Special Topic of Alzheimer's Disease