ARF: I appreciate your taking the time to talk to me.
JT: I am pleased to do this, since, although my major focus as a biomedical researcher is to try to unravel the causes and mechanisms of neurodegenerative disorders such as Alzheimer's disease (AD), I also am dedicated to the mission of trying to help educate the public about the seriousness of these disorders and what research needs to be done to develop cures for them. In fact, I can show you something that was done in an effort to educate the public about some of these disorders, much of the article is relevant to the questions that you sent to me. This was a publication (Connections vol. 7, #2) done by the ADEAR center, the educational arm of the national institute on aging (NIA), about an AD-like disorder known as dementia with Lewy bodies (LB). Part of the text came out of a recent review from our group, but this article was written to make the concepts of the original review much more accessible to the public. The ADEAR article provides an overview of our concept that many neurodegenerative diseases including AD are diseases due to "fatal attractions" between normal or "good" proteins that interact abnormally, precipitate in the brain and cause problems leading to the malfunction of brain cells or their degeneration. Indeed, we think that this is a common pathological or mechanistic theme of many different degenerative diseases of the brain, including those that are common or rare, as well as sporadic or hereditary. I hope this kind of article will improve public understanding of these disorders, since I think it's very important that the public knows as much about these issues as possible so they share the decision-making about how we proceed to find ways to treat the many neurodegenerative disease for which we have no effective therapies at this time.
ARF: Yes, and one of the goals for these interviews is to get people who are really considered to be the thought leaders in the field to talk candidly about what they think the state of the art is.
ARF: So one of the things we were wanting to get, from the horse's mouth so to speak, is your guiding hypothesis. If you had unlimited resources right now, what hypothesis would you be testing?
JT: Well, this ADEAR review is timely since it focuses on LB diseases such as Parkinson's disease (PD), diffuse LB disease (also known as dementia with LB or DLB), etc., and these disorders are prototypical examples of a number of common and uncommon sporadic and hereditary diseases that we include among disorders that are due to "fatal attractions" of brain proteins. Examples of brain proteins that are liable to be involved in "fatal attractions" and cause disease are the presenilins, amyloid precursor protein (APP), tau, synuclein and prion proteins. Some of these proteins have only been discovered very recently because they are involved in diseases such as AD, but others, like tau, were discovered earlier, and we know a lot about what they are supposed to do and so we can carry out more informed experiments of their function-dysfunction when they are either mutated or altered and form aggregates in a neurodegenerative disease.
To be more specific, the notion of fatal attractions is something I think links all of these diseases because these proteins somehow become sticky, bunch together and form aggregates, accumulations of proteins, like a cat unstringing a ball of twine and making a mess in a house where it would trip people up and so forth. I think another analogy one could use, is one that I gave them for the article, and that is the notion that by aggregating, the proteins "gum up" the functions of the cell by blocking the normal movement of organelles and proteins around the cell, which is very fundamental and necessary to the function of a cell much in the way that the flow of traffic in LA is necessary for the city to function. Thus, when the traffic is slowed down, this will bring the city to its knees.
So if that's the case, I think one central hypothesis that needs to be tested is: Are these protein aggregates really the proximal causes of nerve cell degeneration, and, in some cases glial cell degeneration, or are they epiphenomena in the disease? We don't think this is the case with the tau aggregates in the tangles of AD because there are disease causing mutations in the genes that encode tau, APP, the presenilins, prions, and α-synuclein. Thus, it is reasonable to conclude that these proteins, when abnormal, are proximal causes of disease. Indeed, if you have these mutations, you're going to get the disease 100 percent of the time, if you live long enough, and, except for those who die early in life, there are no escapees. Thus, there are several solid reasons that allow us to focus research seriously on these proteins to understand how they lead to nerve cell death.
ARF: What kind of critical experiments you would see needing to be done either to support or refute the hypothesis?
JT: The critical experiments that we and others are trying to do is model these mutant proteins in cells and transgenic mice to see exactly how death occurs. The purpose being to provide formal proof in a reductionist model system, a cell or an animal model, that these proteins may be killers when they aggregate and/or become dysfunctional. We think they are in humans but it would be nice to confirm this in a model system where you can exclude everything else...smoking, lifestyle, what you eat, etc. A lot of people may not need that convincing proof, but it is necessary for drug discovery, and the other very important consequence of such models is that they enable scientist to then dissect the death pathway that is activated by these aggregates so that you can come up therapies or better diagnostics.
For example, it may be possible to develop drugs that prevent the aggregation of disease proteins, or that prevent subsequent or downstream effects of aggregation that activate pathways leading to cell death. Even if such drugs only delay, rather than arrest the disease process, they may be effective therapeutically. Indeed, drugs that delay progression or improve the function of remaining nerve cells in disorders such as AD would be very helpful. To help people understand this concept, it is useful to think of how we treat PD. A well-known patient with PD is Janet Reno, the attorney general. She's had PD for about 5 years I believe, but I see her on TV periodically, and I find it very difficult when I see her on television to appreciate that she has PD. Although PD will continue to lead to the death of nerve cells in her brain that result in motor deficits, and there is no therapy that blocks the killing of nerve cells in PD, drugs like L-dopa are effective therapeutically because they enable the remaining cells to pick up the function of the lost cells. Since we know that it is necessary to lose about 90 percent of neurons in the substantia nigra neurons before a patient shows the motor deficits of PD, if you can make those remaining cells (i.e. 10 percent of the original number of such nerve cells), fill in for the function of the lost cells, then someone like Janet Reno may continue to function very well, and, when this therapy is working optimally, to all outward appearances a patient with PD may seem normal.
On the other hand, since there is no drug for AD that is the equivalent of L-dopa, patients with AD, like former president Ronald Reagan, have a neurodegenerative disease that progresses just like PD even with L-dopa treatment, but these AD patients do not yet have the benefit of a therapy that substantively improves the function of their remaining nerve cells that are involved in memory or cognitive processes.
ARF: Do you think the available drugs for AD, the cholinesterase inhibitors, are serving a similar function in the case of treating AD symptoms?
JT: It looks as though they have an effect, but the effect is rather modest. Thus, I think there is consensus in the field, that we need better drugs that target more encompassing or more fundamental aspects of AD.
ARF: So, in terms of the hypothesis you are focusing on, is it tau as opposed to Aβ? I know there is kind of an artificial distinction there.
JT: Sure, and we're often put into the "tauist" camp, referring to researchers who think that tau is the most important molecule to focus on in AD. However, we are not so narrowly focused in our research, and we also work on β-amyloid, very seriously. We also work on α-synuclein. We'd work on more if we had enough brain space to deal with all the molecules but you can't work on everything and so we have to focus on a couple of things. We believe there's not enough information at this time to rule out tau or Aβ in AD. These are all very hot leads that very much need to be pursued and we do pursue each of these molecules.
ARF: So if you were pushed to have to say, "this is what I think the most likely pathway is..."
JT: Well, I think that's erroneous because AD is not one disease. The analogy that I use is that 50 years ago we thought cancer was one disease, proliferating cells make a cancer so aren't cancers all alike? Well, no. We know that there are different genes that unleash this cell proliferation cascade and, unfortunately, that means that a therapy for breast cancer is different from prostate cancer, different from brain cancer, etc. I mean there are, hopefully, strangleholds you can get on the cancer through one therapeutic approach and the one that was in the news in the summer was angiogenesis. Tumors, like all growing tissues, need a blood supply so if you can strangle the blood supply you can theoretically destroy the tumor. So it would be wonderful if we could find what I call the soft underbelly of the beast we call AD to which we could direct a therapy and kill this horrendous animal we call AD. We haven't identified that yet. It may require several different therapies to block plaques, to block tangles. Certainly for sporadic AD.
ARF: In that regard, to what extent do you think the disease, or diseases, can be classified as primarily genetic?
JT: Even in the genetic form of AD, there are three different genes that harbor disease-causing mutations. Three entirely different genes, and, if you count trisomy 21, three copies of chromosome 21, then there's yet another genetic mechanism. So its very important for everyone to realize that effective therapy for AD is not going to be a single silver bullet, at least I don't think this will be the case. We're still waiting to see if the angiogenesis notion with cancer, a single silver bullet to block blood vessel production, will be effective, and maybe it will be and maybe we'll find something like that for AD but I think in the interim we have to push on with the molecules that you know are important in the pathology and the cell death process. I think it would be foolish of me to say "tau is more important than Aβ."
We even found in recent studies that over 50 percent of familial AD (FAD) brains and over 50 percent of Downs syndrome brains have Lewy bodies. So now I would also have to say that synuclein is playing a role in some way. How all of this gets initiated in FAD, how you get plaques, tangles and LB with an FAD mutation in presenilin I don't know. But there are certainly three bad proteins to deal with and if we could sort out what mutations lead to each of these protein aggregates that would be very very important, but this may not lead to a therapy that's useful for sporadic AD. I think the scientific community appreciates that we should think of Alzheimer "diseases" rather than one disease and the public, I hope, will also appreciate that. There are many forms of this dementia we call AD.
ARF: What would you say is the most common criticism, if there is one, of your major hypothesis or do you think there is something that still needs to be done to address the particular idea that you have?
JT: Even though we worked on tau and plaques and Lewy bodies, we were most identified with tau and tangles and there is fashion in science just like there is in other things. We felt it was important to be highly vocal, almost combative, about not losing sight of tangles. It was not intended to be self-serving or promoting our favorite hypothesis but the field deserves to have the brightest minds in the field working on a diversity of issues. What we felt was bad for the field, and bad for the patients, was to have everyone jump on one bandwagon. I think the fastest way to the discovery of cures or preventatives or agents that will delay disease is a broad front that addresses a number of possibilities. There are some crazy ideas. There are ideas that really haven't gone forward, like the notion of aluminum. We've done some studies ourselves with aluminum, but its hard to see how to take that forward to a therapy. Certainly there are a number of very serious notions, anti-inflammation and a number of things that deserve to be heard and deserve to be funded and pursued.
It was nothing malevolent, people just jump on a bandwagon and think that by following presenilin 1 or presenilin 2 or APP they will get most quickly to the cause. If I were an investment banker or stockbroker I would want to invest in small caps and big caps, perhaps I would invest in the Asian markets, not today perhaps, but 2 or 3 years ago. In other words, you can't give a nickel to everyone but you can certainly do something better than pursuing one molecule. We have been very strong advocates of tau because we felt it was being underexplored. That has changed dramatically this past summer with the discovery of tau gene mutations in frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17), a group of syndromes some of which are very much like AD. Some of the families, in fact, that are now known to have FTDP-17 due to tau mutations were initially considered to have FAD. They look so similar to a clinician that for all the world they would appear to be AD. Not only that, but to pathologists they also have identical tau abnormalities and tau inclusions (neurofibrillary tangles). So it's as close to sporadic AD, I would argue, as FAD due to mutations in APP, PS1 and PS2 is to sporadic AD.
What is the argument that those hereditary diseases are not the disease that Alois Alzheimer described? I think they are close enough and we know there is a lot of phenotypic variability that shouldn't confuse us. We should realize that it's plaques, tangles, now Lewy bodies, nerve cell death and a declining cognitive or motor function that is the essence of these diseases and whether they occur with an aphasia, a speech problem, or a psychosis or what have you, we're talking about diseases that are sufficiently similar that if you solve FTDP-17 I think you're going to solve AD at the same time.
ARF: Its interesting to see how some of those in the amyloid camp are backing off a bit.
JT: Yes, there is nothing like a mutation to crystallize your thoughts. That's the importance of genetics. The fact that the mutation absolutely causes the disease makes it no longer tenable to argue that tau is not important. I don't know that we were necessarily prescient, or what have you, we had amassed ourselves a lot of data which convinced us, so we weren't able to convince other people, maybe we're not very good in making the case...
ARF: Well, I've been rather impressed at how conservative groups are in terms of once they get an idea its very difficult to budge them.
JT: So I think this is going to result...if you look at the neuroscience program this year you'll find no sessions on tau. For the last 5 or 6 years we have fallen into "AD: other" and I think next year you'll see at neuroscience a lot about synuclein, a lot of tau and there'll be tau session I, II and III because it's just got to be a focus.
ARF: Now along that line, would you see tau as being early on in the cascade because of the mutation?
JT: I think you have to. What's the most mysterious, although there's lots not known about the familial dementing conditions, is how to think about linking tau and Aβ into a single pathological cascade and that could be limited imagination on the part of scientists or, more likely, a lack of sufficient biological understanding of these proteins. So we need to know a lot more basic biology and that's not an intellectual sandbox for scientists, it really is the basis from which springs forth new hypotheses about how to look at stuff. You need to have more fundamental understanding of the functions of these proteins and what they normally do and what the dysfunctional consequences of those perturbations are for the cell. That requires basic studies that will then lead to clinical applications, clinical studies, drug discovery efforts and so forth.
ARF: You mentioned before aluminum. Thinking now of other notions that are still out there that would be considered even more marginal than tau used to be, are there any areas that are being currently overlooked?
JT: I think so. Once you have a mutation, it's easy to focus on what those genetic mutations do to a protein. What has been hard for all of us to focus on are the epigenetics, or environmental causes of AD such as head trauma, which is a very robust epigenetic risk factor. It may interact with the apoE4 allele but its still epigenetic. In women who are postmenopausal, the lack of estrogen. Again, all women will go through menopause, some will voluntarily take estrogens and some won't, but if you do you're going to reduce your likelihood of getting AD by 40 percent. These are complicated issues to pursue. In our own laboratory we are pursuing the head trauma risk factor. We looked at this in normal rats as well as in transgenic mice expressing wild-type and mutant APP. Our hypothesis was that head trauma would accelerate AD plaque formation and perhaps induce tangles. None of those things have happened but we've shown that head trauma will induce a massive loss of neurons in the PDAPP mice, i.e. those that form plaques (as in AD) due to the overexpression of mutant APP.
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