What’s lost: a healthy brain slice (left) and one with Alzheimer’s.
Tau tangles or amyloid plaques. Pick your poison.
Of the many advances in Alzheimer’s research to which Penn scientists have contributed over the last 20 years, none, arguably, has been as significant—or involved as much perseverance—as the efforts by Lee and Trojanowski to move the focus of research back in the direction of tau. They were the first to discover, back in 1991, that the tangles in Alzheimer’s were formed of tau proteins, and they have continued to make important discoveries in that area despite a movement toward research involving beta-amyloid plaques.
“There used to be a joke back in the ’90s that it was a religious debate,” Kurt Brunden is saying. “You had the Baptists—the beta-amyloid peptides—versus the tauists, right? John and Virginia have always clearly been in the tauist camp. John I would say is a pure tauist. Virginia is a tauist with an acceptance of the Baptist religion. She recognizes that the amyloid beta does play a role—and John grudgingly so, probably. But they were clearly at the forefront of the tau ideas.
“Back in the ’90s, or even the late ’80s, they were fighting an uphill battle, because everyone at the time was focusing on a-beta peptide,” he adds. “And in the scientific community, to persevere, sometimes you have to have some thick skin to keep selling your point when the others are naysayers.”
Tau’s main function in the nerve cell is to assemble and stabilize microtubules, which can be likened to train tracks or interstate highways in the way they allow proteins to be transported within the cell. Each neuron has an axon, a long fiber that conducts electrical impulses that act as messages, sort of like a fiber-optic cable.
Back in 1994, “John and I hypothesized that because tangles form in nerve cells, perhaps that kicks tau away from its normal function, which is to stabilize the microtubules,” says Lee. “If the microtubules—that interstate highway—collapse, then soon no transport occurs. And then people in the small town will starve to death, right? So if the microtubules stop working, eventually the axon will collapse, and then the neuron will die. So we thought, ‘OK, if you can stabilize this microtubule, maybe you can retard the degeneration of the nerve cells.’”
But tau and its tangles got short shrift for a couple of reasons. For one thing, the gene that produces beta amyloid—the APP, or amyloid precursor protein—had already been discovered in 1984, giving researchers something very tangible to work with.
“Families have mutations on the APP gene that are inherited,” Lee explains. “You have two copies of your gene; you get one bad copy from either of your parents, and you will get the disease. So that’s huge in terms of implicating that pathway, or that protein, in a disease.”
Furthermore, while nobody was denying that tau was the stuff of tangles, tau aggregates were found in the brains of patients with other, non-Alzheimer’s neurodegenerative diseases as well. That led some to argue that the tau tangles were a reaction to beta amyloid, not a primary cause of Alzheimer’s. Even when tau mutations were identified in patients with frontotemporal lobar degeneration (FTLD), proving that tau tangles alone can cause a neurodegenerative disease, notes Lee, “people say, ‘Fine. But that’s a different disease.’”
As a result, researchers in the academic community and in the pharmaceutical industry “would rather focus on beta amyloid,” says Lee. “Because so many people are working on the biology of APP and also the production of beta amyloid, we know a lot about the process of amyloid production. We know the identity of the enzymes. And when you have enzymes, pharmaceutical companies are very, very happy. They can inhibit these enzymes and see whether they can reduce production of beta amyloid.”
But, she adds, “they’re having a lot of problems with that approach.” In one clinical trial that began in 2000, patients developed complications; some died of Alzheimer’s. And yet when pathologists examined their brains, “the amyloid, by and large, in specific areas, are cleared.” In other words, they succeeded in getting rid of the amyloid plaques—but it hadn’t done any good.
“We now realize that Alzheimer’s disease actually starts very much earlier than the symptoms appear,” she says. “So you can get rid of plaques. But the reason the patients are not improving could well be because the [tau] tangles are already there, and they’re not going away. They’re really targeting the neurons to die.”
One result of that “Baptist” dominance was that whenever an Alzheimer’s conference was held, nearly all of the sessions were “filled with people studying beta amyloid or APP processing and so on,” says Lee. “So the amount of funding, the number of scientists that work on beta amyloid versus tau, is like 10 to one.
“Science is like anything: there’s fashion,” she adds. “People have the mass mentality.”
“There’s over a billion dollars that pharma is spending on clinical trials,” says Trojanowski. “But almost all of them—hundreds of them—are focused on a-beta. I think three or four are focusing on tau. A-beta was a good bet, a very popular target, beginning 10 years or so ago. But there’s been some dramatic failures of clinical trials that put into question the a-beta cascade hypothesis, which explains all Alzheimer’s disease by virtue of the accumulation of a-beta. And while we acknowledge the importance of that hypothesis and the benefits that may accrue from shutting down a-beta,” those benefits have not yet occurred.
“We have made the case for years that there should be an equal investment in tangles as targets for fundamental research, but also for drug discovery,” he adds. “Companies are beginning to see the wisdom of going after tau pathology with drugs.”
The first drug that Trojanowski and Lee proposed to replace the lost tau was Taxol, a cancer drug that binds microtubules and thus blocks mitosis (cell division).
“We actually had a patent issued in 1996 for Taxol, and we showed Taxol did work in a mouse model,” says Trojanowski. “But we couldn’t improve its pharmacology so that enough got into the brain to be a usable drug.”
So, with the help of Amos Smith, the Rhodes-Thompson Professor of Chemistry, they tried something else: another family of microtubule-stabilizing drugs called epothilones. One in particular, epothilone D, has worked in mouse models, and can cross the blood-brain barrier. The only catch is, somebody else has the patent on them.
“Unfortunately for us, there’s a small company, Kosan, that owned the intellectual property for epothilone D,” says Lee. “It was bought by Bristol-Myers Squibb two years ago. And they are quite aware of our work.”
As a result, “we at the University may not make a gazillion of dollars,” she adds. “But it’s OK, if we’re going to help people. So we are actually working with Bristol-Myers Squibb to try to help them with the clinical trial. They’re very happy with our results.”
“We’re pleased and proud that what we had conceptualized and proposed as a therapy is going forward,” says Trojanowski. “The experiments with epo D in mice were our experiments. We did them. Bristol-Myers Squibb has done them as well.” It’s always possible that epo D “could crash, like other therapies, but at least it will get its day in court, if you will, in a clinical trial,” he adds. “So that is very, very exciting. If it’s successful, it will hopefully bring more stakeholders—pharmaceutical companies, biotechs—into the game.”
Mar | Apr 2011 contents