Virginia Lee & John Trojanowski on the Protein Road Map to Alzheimer's
Special Topic of Alzheimer's Disease Interview, December 2011
"So when you get a sequence read of amino acids forming the paired helical filaments that Virginia purified directly from Alzheimer brains that tell you this is the letter code for the tau protein, this is definitive that tau forms these filaments, there's no question...and that was our 1991 Science paper, which resolved a raging controversy at the time and that set the field straight on what the building blocks of tangles were."
Tau was quite the controversial discovery, as many researchers at the time felt that the beta-amyloid peptide was the answer to unlocking the secrets of Alzheimer's. The differences between the two schools of thought were likened to a holy war, between the "BAPtists" (those who espoused the beta-amyloid protein theories of Alzheimer's) and the opposing "Tauists."
Trojanowski explains, "The religious play on words for these competing hypotheses of what led to brain degeneration in Alzheimer's disease was a cute thing, but it really did verge on the intensity of religious wars—it could get very harsh. But over the years that has changed. There were people who said that A-beta explains everything, and then when it didn't, they said, maybe A-beta is necessary but not sufficient; it's the trigger.
"So then you have to think of a bullet in a gun. You pull the trigger and the bullet goes out, but if you start trying to fix the trigger, that's not going to do anything about where that bullet is heading. So if jiggling A-beta doesn't cure the disease, that's because it may be the trigger and not the bullet that actually kills neurons in Alzheimer's disease.
"When we started, Glenner and Wong had already identified the beta-amyloid peptide that forms Alzheimer's disease amyloid or senile plaques, and so people were just starting to wonder about the tangles: could the protein be tau? Using brains we had collected in our center, we were able to demonstrate that Alzheimer tangles indeed were formed by abnormal tau proteins."
–Virginia Lee
"I have to say it's enormously gratifying to me that we espoused the tau hypothesis if Alzheimer's disease neurodegeneration not only because we believed in tau as a therapeutic target for Alzheimer's disease drug discovery, but also, back in the dark period of tau, 10 years ago or so, when no one, absolutely no one, believed that tau had anything to do with Alzheimer's, we really had to make a ruckus and remind people about tau."
Lee agrees, saying that even the most devout BAPtists will generally now admit that tau plays a role in Alzheimer's brain degeneration.
Trojanowski likens tau to the cross-ties on train tracks in the brain's essential transportation network. "If you flip those off, the tracks fall apart, the trains crash. All this is grounded in a very solid scientific, preclinical, basic understanding of the function of tau. Of all the neurodegenerative disease proteins, tau's normal functions are the most well understood. When you think about drug targets, you either want to try to block a pathology that gains toxic properties or you can replace the function of the disease protein that gets clumped up in a tangle or a plaque.
"We actually have a program that's trying to correct the loss of the function of tau due to its sequestration in tangles by giving a drug that binds to and stabilized microtubules (the train tracks of neurons) in the absence of tau trapped in tangles, so this strategy can make up for the lost function of tau.
"I think we have the only program—it was certainly our idea, our very first idea for tau therapy that we published in an hypothesis paper in 1994 (Lee VM-Y, Daughenbaugh R, and Trojanowski JQ, "Microtubule stabilizing drugs for the treatment of Alzheimer's disease," Neurobiol. Aging, 15:S87-S89, 1994)—to think of a drug discovery program that makes up for a loss of tau function. Everything else in clinical trials now is dealing with the gain of toxic function, blocking plaque toxicity, blocking oligomer toxicity, and so on."
Another key discovery made by Lee and Trojanowski was the importance of alpha-synuclein. Their 1997 paper in Nature on the topic (Spillantini MG, et al., "alpha-synuclein in Lewy bodies," 388[6645]: 839-40, 28 August 1997) is another blockbuster, with over 2,000 cites in the Web of Science®. Although a big discovery in terms of Parkinson's disease, it is also involved in Alzheimer's because of the fact that 50% of Alzheimer's patients also exhibit Lewy body pathology like that seen in Parkinson's disease.
"The religious play on words for these competing hypotheses of what led to brain degeneration in Alzheimer's disease was a cute thing, but it really did verge on the intensity of religious wars—it could get very harsh."
–John Trojanowski
"One hundred percent of Parkinson's disease patients have Lewy body pathology, but the incidence of Parkinson's is much lower than that of Alzheimer's, so the 50% of Alzheimer's patients with Lewy body pathology is actually the largest pool of patients with pathological accumulations of alpha-synuclein inclusion, more so than Parkinson's patients," Lee explains.
This crossover can be beneficial for research in both groups, particularly when it comes to pharmaceuticals. "I use this economic argument to try to persuade pharmaceutical companies that they will not only have a market for Parkinson's but also for Alzheimer's if they target alpha-synuclein in Lewy bodies for drug discovery," Trojanowski explains, "Here's a market now for 3 million patients: you can treat 1 million Parkinson's patients and 2 million of the 4-4.5 million Alzheimer's patients who harbor alpha-synuclein Lewy bodies in their brains as well as A-beta plaques and tau tangles."
"You can use this argument for other drugs as well," Lee adds. "Synuclein drugs can treat Parkinson's and Alzheimer's, and tau drugs can treat Alzheimer's and other tau-related diseases, like progressive supranuclear palsy or frontotemporal degeneration."
"We're trying to get pharmaceutical companies to treat some of these orphan diseases like progressive supranuclear palsy and frontotemporal degeneration by showing them that if you add Alzheimer's patients too, you have a market. This is part of our patient advocacy as well as our true scientific belief in what the problems are in Alzheimer's and other related neurodegenerative diseases," says Trojanowski.