The diseases are different, but the pathologies are surprisingly similar. At the pathological core of Alzheimer’s disease, Parkinson’s disease, and perhaps a half-dozen other neurodegenerative disorders and dementias are misfolded proteins that gradually accumulate within the brain—the amyloid plaques or neurofibrillary tangles of Alzheimer’s disease, for instance, and the Lewy bodies of Parkinson’s. These pathologies develop insidiously over years or decades, and can manifest themselves clinically as dementia, memory loss, and movement disorders. Exactly how and why this happens, however, remains among the most pressing questions in all of neuroscience.

"As far as we know, almost all neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain or spinal cord," says Virginia M.-Y. Lee of the University of Pennsylvania.

The past decade has seen a revolution in the understanding of the common pathogenic mechanisms at the heart of these neurodegenerative diseases. Among the leaders of this revolution has been the University of Pennsylvania neuroscientist Virginia M.-Y. Lee, whose work on the pathology of the tau protein and the nature of Lewy bodies in Alzheimer’s has propelled her to the current rank of #12 among the most-cited authors in neuroscience over the last ten years, according to Thomson Scientific’s Essential Science Indicators. Lee’s seminal 1991 Science paper that resolved the controversy over the building blocks of Alzheimer tangles by demonstrating that paired helical filaments are formed from tau has been cited more than 860 times (V.M.-Y. Lee, et al., Science, 251[4994]: 675-8, 1991). More recently, her 1997 Nature article, "Alpha-synuclein in Lewy bodies," has received more than 1,000 citations (see accompanying table), and 40 of her papers published in the last decade have each attracted 100 or more citations.

Lee began her career studying music at the Royal Academy of Music in London. In 1968, she received her Master’s of Science in biochemistry from the University of London and then her doctorate in biochemistry in 1973 from the University of California at San Francisco. After a postdoctoral year at the University of Utrecht, she spent five years in experimental pathology at Harvard Medical School, followed by a year at the pharmaceutical firm then known as Smith Kline & French (now part of GlaxoSmithKline) in Philadelphia. In 1981, Lee moved to the University of Pennsylvania School of Medicine, where she is now a full professor and Director of the Center for Neurodegenerative Disease Research as well as Co-Director of the Marian S. Ware Alzheimer Drug Discovery Program. Along the way, Lee also received an MBA degree from the University of Pennsylvania’s Wharton School in 1984.

Lee spoke to Science Watch from her Penn office in Philadelphia.

Your early research was on the neurofibrillary tangles of Alzheimer’s disease and identifying the tau protein as the primary component, but now you work across the board of neurodegenerative diseases. Why the broader scope?

I am a director for the Center for Neurodegenerative Disease Research at the University of Pennsylvania, and our mission is to identify the proteins that become misfolded in common as well as rare neurodegenerative diseases, in order to hasten development of informative diagnostics and drug-discovery efforts. These diseases include Alzheimer’s, Parkinson’s, frontotemporal dementia, known as FTD, and amyotrophic lateral sclerosis, or ALS. As far as we know, almost all neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain or spinal cord. Our approach has been to isolate these proteins from the brain, starting with tau, and try to understand why they become misfolded and why they accumulate, and then to develop models to study them—both test-tube models and animal models. Eventually, we hope to come up with therapies and better markers for diagnosis.

Are the misfolded proteins the only common theme in these diseases?

No. Aging is a risk factor for these neurodegenerative diseases, and given the current longevity revolution, it’s not surprising that if you develop one neurodegenerative disease, you’re more likely to get one of the others. In the later stages of Alzheimer’s, for instance, patients are likely to get a Parkinson’s-type movement disorder, and vice versa. Parkinson’s disease patients in the late stage often get dementia, sometimes of the Alzheimer’s type, and sometimes other forms of dementia. We recently published a paper in Science reporting a connection between frontotemporal dementia and ALS disease (M. Neumann, et al., Science, 314[5796]: 130-3, 6 October 2006). One of the reasons we started studying FTD is that some of the patients, about 40%, have tau pathology. That’s not specific to Alzheimer’s; it’s also found in many other diseases. And it’s found particularly in FTD, where mutations in tau genes have been identified in families with this kind of dementia.

What causes the initial protein misfolding in these neurodegenerative diseases?

That’s the million-dollar question, and the answer is, we really don’t know. It could be a lot of things. It could be environmental factors. It could be oxidative stress. For patients with genetic mutations, it’s been shown, at least for tau, that these mutations can facilitate aggregation. Most likely it’s multiple factors. For example, one thing we did notice, particularly for proteins that accumulate inside cells, inside neurons—like tau and the synuclein protein that forms the Lewy bodies of Parkinson’s disease—is that they have very slow turnover rates. Some proteins can turn over in 20 minutes, others turn over in hours. Tau and synuclein, on the other hand, turn over in days. Whether that has anything to do with the propensity of these proteins to misfold and to aggregate, we don’t know. But this observation, as well as the fact that these proteins readily fibrilize in vitro, may be relevant. Also, tau and synuclein are very abundant proteins. There are a lot of these proteins inside cells, and that also may be a factor, since protein concentration is a critical determinant of fibril formation. What’s really strange is that, when they’re in solution, they generally don’t have much structure. They’re soluble proteins, which is somewhat counter-intuitive. You’d think that the more insoluble they are, the more likely they would end up making tangles. But these proteins are very soluble. They have almost no structure, and yet under some circumstances they somehow fibrilize and turn into presumably toxic fibrils that eventually fill up the cell and compromise cell viability. Hence, blocking fibrilization or eliminating misfolded proteins have become targets for drug discovery for Alzheimer’s, Parkinson’s, and related disorders.

Alzheimer’s researchers have always concentrated on the amyloid protein and plaques as the cause of the disease. How long did it take to convince people that the tau protein played a significant role in Alzheimer’s? And what was the evidence that finally changed people’s minds?

Highly Cited Papers by Virginia M.-Y. Lee and Colleagues, Published Since 1997 (Ranked by total citations) Rank Paper Citations 1 M.G. Spillantini, et al., "Alpha-synuclein in Lewy bodies," Nature, 388(6645): 839-40, 1997. 1,099 2 M. Baba, et al., "Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies," Am. J. Pathology, 152(4): 879-84, 1998. 466 3 V.M.-Y. Lee, et al., "Neurodegenerative tauopathies," Ann. Rev. Neuroscience, 24: 1121-59, 2001. 393 4 B.I. Giasson, et al., "Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions," Science, 290(5493): 985-9, 2000. 391 SOURCE: Thomson Scientific Web of Science

Oh boy…I guess the beginning for us was when we showed back in 1991 that tau is the building block of the abnormal filaments in Alzheimer’s neurofibrillary tangles at the amino-acid-sequence level, but it took many other steps forward, not just one, to generate interest in the tau-mediated Alzheimer neurodegeneration hypothesis that we proposed in the early 1990s. One major factor that convinced people that tau is really important, at least for causing cells to die, was the identification by a number of laboratories of mutations in the tau gene in FTD. This was in 1998, and was the strongest evidence. The second factor was that many researchers have over-expressed the amyloid precursor protein in mice, and these mice develop beta amyloid plaques. They don’t elicit a tau response, however, and their neurons don’t die, even though these mice have a head full of plaques. You don’t see the phenotype of neuron death. This gave rise to the hypothesis that beta amyloid is necessary and essential, but something else must also be required for neurons to die. We think what’s required is tau. It may be downstream to the beta amyloid accumulation, but it’s required for neuronal death. It’s very interesting that, in mice, we can disassociate these two phenomena. You can make a tau transgenic model and demonstrate that the neurons do die, and you can generate a beta amyloid mouse and you can’t show neuron death. Individuals with FTD have tau but not amyloid and the neurons do die.

To give you an example of how the mindset has changed about tau, all of a sudden scientists in the pharmaceutical companies, all the big pharmas, are focusing on different pathways from beta amyloid, and they’ve realized that they cannot ignore tau. It’s really part of the pathogenic pathway leading to neuron death in Alzheimer’s disease.

Why did tau and neurofibrillary tangles take a backseat until 1997?

Everybody wanted to identify the disease proteins in plaques and tangles. The protein amyloid beta was identified by sequencing in 1984, and the gene was quickly cloned. Then, several years later, the mutations on the amyloid precursor protein gene were identified. All this led us to believe that beta amyloid was quite important. It was about the same time, in 1985, that people using antibodies to tau were able to demonstrate that the tangles might be composed of the tau protein. Previously they thought that it was neurofilament in the tangles. That’s why I was involved. The problem with the idea of tau as a disease protein important for Alzheimer’s was the observation that tangles are found in many, many different diseases. It made people wonder if it was just a generic, nonspecific response to injury. In 1998, when three independent groups led by Jerry Schellenberg, Michael Hutton, and Maria Spillantini identified the mutations in the tau gene, they validated the fact that tau by itself can cause disease and cause neurons to die.

Tell us about Lewy bodies and the similarities with tau and Alzheimer’s.

Lewy bodies are made out of another protein, alpha-synuclein. The only similarity between alpha-synuclein and tau is the biochemical properties. They’re very stable and very soluble proteins. They don’t have much in the way of structure, and they’re very abundant. They were both identified first by biochemical methods, and the genes encoding them were later sequenced, which subsequently enabled pathogenic mutations in these genes to be discovered, thereby implicating these genes and the mutant proteins they encode in mechanisms of disease. In other words, the quickest way to look for a disease protein is to use families that have the disease, then do the sequencing and identify the mutation in the genes. The mutation in alpha-synuclein was identified in 1997 in a large family, and then we collaborated with Michel Goedert and Maria Spillantini in England to show very quickly that these proteins are the building blocks of Lewy bodies in Parkinson’s disease brains.

Is the death of neurons required for dementia?

That’s somewhat debatable. Some people feel you can have a slight change, a slight loss of memory without neuron loss. Obviously we don’t know. There’s no good way of studying a function like this in humans. The best you can do is correlate what you see by imaging—MRI, for example—with the clinical phenotype. With Alzheimer’s, we’re beginning to be aware that even patients with very mild cognitive impairment already have Alzheimer pathology —that is, abundant plaques and tangles. Yet, they’re not totally demented. What that indicates is that you need a certain threshold of neuron dysfunction and death before you have the bona fide phenotype. There may be a certain amount of brain reserve that protects us from profound dementia and memory impairment. It’s a similar case in Parkinson’s disease; that’s why the imaging of dopaminergic cells, the vulnerable cells in the disease, is not a good diagnostic test. Patients can be perfectly, absolutely normal, and have no movement disorder whatsoever, even though they’ve lost a third of their dopaminergic neurons. In animals, by contrast, there’s a lot of data suggesting that there can be some form of dementia or memory impairment or movement disorder that may or may not predate neuron death. In people, there may be abundant Alzheimer amyloid plaques with few or no tangles, but these individuals may not have dementia, and this is referred to as "pathological aging."

We just completed a biochemical study (Forman, et al., Neuroscience, in press) in which we examined postmortem brain samples from patients with Alzheimer’s or a clinical diagnosis of mild cognitive impairment, and we noted that there is considerable overlap in the levels of pathological tau and A(beta) using biochemical methods, and this also has been seen using immunohistochemical and histochemical methods. In general, however, while there may be a few patients with mild cognitive impairment who have little or no Alzheimer pathology, most patients with mild cognitive impairment have pathology just like late-stage Alzheimer’s disease. Hence, the important take-home message is that we need to develop diagnostics to detect earlier prodromal stages of Alzheimer’s disease to optimize the possibility of developing drugs that will abrogate Alzheimer neurodegeneration before the brain is irreparably damaged and cognitive functions are lost.

Where do you see the research in neurodegenerative diseases going in the next few years? And what are you focusing on?

Research on Alzheimer’s disease is obviously the most mature of all the neurodegenerative diseases we study—there are so many people working on it. The field should be quite proud of the progress made. It’s really poised to develop novel therapies. We now have biomarkers that are being validated, both in the central nervous system and in the blood, and also techniques to image amyloid plaques. Those will develop into even more sophisticated technologies and give better and earlier diagnosis of Alzheimer’s disease. That in turn will help us come up with therapies by helping us to determine efficacy. 

Our work in Alzheimer’s is more applied now, more translational than basic science, but the basic science continues, given the necessity to elucidate mechanisms and pathways of neurodegeneration to gain a fuller understanding of those processes that are most critical to its onset and progression. It’s a more mature area, and we think that although we’re far from having perfect knowledge at this time about all of the mechanisms underlying rare and common neurodegenerative disorders, we certainly know enough to embark on aggressive efforts to develop more effective therapies for these disorders. With Parkinson’s, we are in the process of coming up with better models. There are good models for Alzheimer’s disease and a lot of understanding of basic mechanisms, but this isn’t yet the case with Parkinson’s. So we’re developing models, and making sure they can be useful, so that when we do have potential therapeutics, we can use these animal models to look at efficacy. 

In FTD and ALS, as I mentioned, our team just identified TDP-43 as the disease protein that is common to both conditions, and there’s a lot of work to be done on it. What does it do? Why does it become abnormal? We’re generating models so we can try to understand the connections between the movement disorder, the motor neuron disease, and dementia. Underneath it all, we’re trying to understand the bigger picture: How does dementia relate to movement disorders? Why are there so many proteins that can cause dementia and also movement disorders? That’s ultimately what we want to find out so that we can translate these insights into meaningful therapies to arrest or modify disease for the benefit of the increasing number of individuals in our aging society who are otherwise fated to succumb to these disorders. Indeed, our wildest fantasy is to develop strategies for successful brain aging, be they pharmacological or lifestyle practices, that will usher in an epoch free of Alzheimer’s, Parkinson’s, ALS, FTD, and so on—just as was done 50 years ago with the conquest of another debilitating and often fatal nervous-system disease, polio, which many younger individuals no longer recognize as the scourge it once was.   

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