George Perry on the Role of Oxidative Stress in Alzheimer's Disease
Special Topic of Alzheimer's Disease Interview, June 2011
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The last couple of years we have focused on mitochondria. We've been looking at dynamics of mitochondria—autophagy and fusion-fission balance. We've also examined steroid sex hormones, leptins, and changes in cell-cycle reentry. These studies led Xiongwei Zhu, Mark A. Smith, and myself to coin the idea of the two-hit hypothesis of Alzheimer's disease.
What is the two-hit hypothesis of Alzheimer's?
The idea is that in order to have Alzheimer's, you need more than one abnormality. You need, say, oxidative abnormalities and cell-cycle reentry abnormalities, much like you need multiple hits in cancer. That was published in Lancet Neurology in 2004—"Alzheimer's disease: the two-hit hypothesis," (Zhu XW, et al., 3[4]: 219-26, April 2004).
What do you see as the role of cell-cycle reentry in Alzheimer's disease?
It plays a role in cell death. We have made a transgenic model, recapitulating cell-cycle reentry in post-mitotic neurons. In that case you find cells dying. So by itself, cell cycle reentry can push hard enough to cause cell death. The two-hit hypothesis suggests that cell-cycle reentry, together with oxidative stress, and maybe other metabolic abnormalities, all have to occur together to have cells lose function and die. Alzheimer's disease isn't just one thing.
So how would you approach preventing Alzheimer's or slowing its progression considering your perspective on the processes involved?
For right now, lifestyle modification.
OK, what lifestyle modification would you recommend?
"With my colleague Mark A. Smith, also a highly cited person who unfortunately died in December, we've written probably about 100 publications questioning the amyloid-cascade hypothesis."
View a ScienceWatch.com tribute to Mark A. Smith.
Exercising, eating a proper diet, being socially involved, taking the advice your grandmother might have given you. All those types of lifestyle changes can reduce incidence by about half. It doesn't completely protect you, but that's the best we can do at this time.
What do you see as the role of exercise?
I think exercise and being mentally active, among other things, changes metabolism throughout the body, hormone balances, etc. If I had to make one guess at this point, I'd say Alzheimer's disease is a metabolic disease.
Are you involved with any pharmaceutical approaches to controlling this disease?
We do have some. We work very closely with the pharmaceutical industry. Some of the ideas come out of the pharmaceutical industry—leptin and sex hormones, for instance.
The idea that leptin is regulating metabolism?
Regulating fat levels.
Doesn't insulin fundamentally regulate fat levels?
That's also part of the same thing. We don't directly work on insulin, although one of my collaborators, Paula Moreira, does, studying the relationship between insulin and amyloid. There's a lot of crosstalk and interplay. I edit a journal, the Journal of Alzheimer's Disease, and we had an issue on just that topic—Alzheimer's and diabetes. I think it's still an emerging area. The degrading enzyme for insulin also degrades amyloid beta. And my own view is that amyloid beta is a molecule at the crossroads of brain aging and repair.
What is the focus of your research now and for the next few years?
What I'm trying to do is look at changes in mitochondrial metabolism, modifying oxidative balance. I know it's much more complicated than lowering oxidative stress. We understood that a long time ago. Back in the early 1990s I thought of oxidative stress as a signal transduction pathway from my studies of sea urchins in the 1970s, not necessarily a damaging pathway. In Alzheimer's disease, when people take large amounts of antioxidants, we see mixed results. Some people may benefit, some people may deregulate signal transduction pathways and be at greater risk of death.
We're also doing a lot of work now on the heart. I think there's a connection between the heart and the brain that has not been investigated yet in Alzheimer's disease. If it's a mitochondrial problem, we know we can model that in fibroblasts from the skin. Then there should be other places in the body that are highly energetic, that have the same changes as the brain and maybe were missed in prior work because no one knew what to look for.
So we're looking at the brains from people with heart disease and trying to get hearts from people who had Alzheimer's. My feeling at the moment is that when we look at diseases of aging there are few clues as to why they come about, or what the treatments should really be. Everybody's trying to come up with simplistic ideas that do not address the elegantly pleotropic aspects of aging and Alzheimer disease.
What do you think of the idea that the anti-amyloid drugs failed because they didn't get to the disease early enough?
"Our hypothesis is that oxidative stress is a window for looking at the disease, just as amyloid is also a window."
People with Alzheimer's disease have heterogeneous amounts of brain damage. Some have massive neuronal loss; some have minimal. And when the amyloid was removed with the vaccine, why didn't some people get better? Why is it that none have responded?
Is it true that these drugs can actually remove the amyloid in the brain?
That's very well shown for many people. It's quite clear. But remove the amyloid, people don't get better. If anything, they get worse.
What key questions about Alzheimer's would you most want to have answered by your research in the not too distant future and ideally as quickly as possible?
The primary question I would like answered is the exact cellular and chemical mechanism responsible for oxidative damage in Alzheimer's disease. Is it altered metal homeostasis resulting in changes in mitochondria autophagy?
Other questions I'd like answered: what is the role of lipofuscin, which also accumulates in Alzheimer's disease? It is not just undigested stuff. That idea comes from storage diseases. They could be detox centers to hold metals. Another issue is insolubility. Why are neurofibrillary tangles and senile plaques insoluble? Is it because of oxidative crosslinks? What are plaques and tangles really made of? Tau and amyloid beta have never quantitatively been analyzed in lesions.
Then I'd like to know when does Alzheimer's disease begin? What is the critical phase shift that changes a person with amyloid beta into an Alzheimer's disease case? Is it the combination of insults like we consider in the two hit hypothesis or is it something specific? How does it depend on aging? Is it dependent or distinct? Careful analysis of sporadic and even more genetic cases followed in relative youth could clarify this question. Understanding if AbetaPP/PS1-PS2 mutant-carrier people are exactly the same as sporadic is critical.
Our view is that genetically caused disease results through inappropriate deployment of the amyloid beta response, so that it does not protect the brain from aging, or the inappropriate response actually screws things up. Amyloid beta may be one of the most critical response elements to brain aging, not just in Alzheimer's disease, but instead a major part of how we protect our most important organ.
George Perry, Ph.D.
Department of Biology
University of Texas at San Antonio
San Antonio, TX, USA
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GEORGE PERRY'S MOST CURRENT MOST-CITED PAPER IN ESSENTIAL SCIENCE INDICATORS:
Nunomura A, et al., "Oxidative damage is the earliest event in Alzheimer disease," J. Neuropathol. Exp. Neurol. 60(8): 759-67, August 2001 with 555 cites. Source: Essential Science Indicators from Clarivate .
ADDITIONAL INFORMATION:
- View images from the following events with George Perry:
- ScienceWatch.com Pays Tribute to Mark A. Smith
KEYWORDS: ALZHEIMER’S DISEASE, OXIDATIVE STRESS, CYTOSKELETAL ABNORMALITIES, CALCIUM, CONTEXT, ENVIRONMENT, AGING, AMYLOID, DISEASE RESPONSE, ADAPTIVE VALUE, COPPER, IRON, REDOX CYCLING ELEMENTS, MITOCHONDRIA, AUTOPHAGY, FUSION-FISSION BALANCE, STEROID SEX HORMONES, LEPTIN, CELL-CYCLE REENTRY, TWO-HIT HYPOTHESIS, LIFESTYLE MODIFICATION, , DIET, EXERCISE, SOCIALIZATION, METABOLISM, FAT LEVELS, DIABETES, INSULIN, HEART, LIPOFUSCIN, STORAGE DISEASES.
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