Prof George Perry: Perspectives on Alzheimer’s Disease Research – Part 1
Key role for oxidative stress
21 Jan 2016
Editorial article
With over 1000 publications, Prof George Perry is recognized worldwide as an expert in the field of Alzheimer’s disease research. As Dean of the College of Sciences at the University of Texas at San Antonio, he is Professor of both biology and chemistry, holds a Semmes Foundation Distinguished University Chair in Neurobiology and also serves as Editor-in-Chief for the Journal of Alzheimer’s Disease. In part one of this exclusive interview SelectScience® spoke to Prof Perry about the innovative research from his lab.
Prof Perry’s research career has encompassed a broad variety of topics but has focused mainly on the role of oxidative stress in Alzheimer’s disease. Although oxidative stress is now considered a major underlying feature of this chronic, neurodegenerative condition, little was known of its contribution when Prof Perry began his career. Trained as a marine biologist, he had a very different approach to the study of oxidative damage in Alzheimer’s disease and was among the first to show that these oxidative abnormalities occur early and that they are a marker of the transition of the brain from a normal to neurodegenerative state.
Oxidative stress is an early marker of Alzheimer’s disease
Oxidative stress refers to the damage caused by reactive oxygen species to cell machinery and function. Disturbances in the levels of oxidizing species may arise from overproduction, impairment in clearance mechanisms, or a combination of both. Alzheimer’s disease is associated with a number of pathologies including plaque formation, neurofibrillary tangles, oxidative damage and inflammation. Despite a huge body of research, the underlying causes of Alzheimer’s disease are yet to be elucidated and no successful therapies have been developed.
We adapted techniques to look at oxidative changes at the cellular and subcellular levels. Prior work took tissue and ground it up and looked at the average changes, which are not very useful.
Prof. George Perry
University of Texas at San Antonio
Prof Perry’s pioneering work involved the use of high resolution microscopy combined with histochemical techniques that enabled localization and quantitation of markers of oxidative stress. Light and electron microscopy were combined with chemical assays to produce reliable data that could detect exactly where and how much change was occurring.
“We adapted techniques to look at oxidative changes at the cellular and subcellular levels. Prior work took tissue and ground it up and looked at the average changes, which are not very useful. The brain is very complex at a microscopic level, every cell does something different, each part of the cell does something different, so if you balance everything out and average it, you may find very little change, when in fact there are tremendous changes occurring.”
High resolution microscopy
New advances in technology are now being used to examine the generation of free radicals at the atomic level, investigating how they cause neuronal damage with greater resolution. Prof Perry’s lab have used atomic resolution microscopy to show that copper and iron are involved in redox pathology and that they are differentially distributed in the hallmark plaques and tangles of Alzheimer’s disease. This was predicted by previous studies but technological limitations meant metals were detected indirectly. However, new atomic resolution microscopy allows localization of all the metals present. Copper and iron are known to catalyze oxidative abnormalities, with further study showing that amyloid-β binds copper, affecting its redox activity. This data has prompted Prof Perry to propose that amyloid-β is able to suppress copper mediated mechanisms of oxidative damage. Recent data from the Perry lab suggests that amyloid-β has a role in modifying iron metabolism, through binding copper and acting as a ferroxidase. “A lot more work has to be done - using high resolution techniques a mechanism has been pointed at, but we haven’t pinned it down completely yet.”
This work is linking oxidative stress mechanisms with amyloid plaques in an unexpected manner, with amyloid-β implicated as having a protective role. Currently, several studies are targeting amyloid-β removal as a therapeutic strategy but the effectiveness of those trials is called into question by findings such as these.
Read about Prof Perry’s concerns for the future of Alzheimer’s disease research in part two of this interview here.