Researchers Eye Role of ‘Infectious’ Proteins in Neurodegenerative Disease


by Jim Schnabel

July 29, 2009

It’s not clear how the tangles of the protein tau commonly seen in people with Alzheimer’s disease spread throughout the brain in the course of disease—and to a modest extent in ordinary aging. But European researchers recently described an experiment in transgenic mice in which extracts containing tau tangles appeared to induce the formation and spread of new tangles in otherwise healthy mouse brains.

The findings seem most immediately relevant to Alzheimer’s disease and are consistent with other evidence suggesting that “once the tau pathway has started, for whatever reason, it probably becomes self-sustaining,” says Michel Goedert, a neuroscientist at Cambridge University who helped to lead the study, published online June 7 in Nature Cell Biology.

Most Alzheimer’s researchers had been targeting the buildup of beta-amyloid, a sequence of amino acids that form plaques in the brains of people with the disease. But experimental anti-amyloid drugs have shown little or no effect in stemming the disease in people, even where there is evidence that they have cleared amyloid from the brain.

Many researchers now believe that in people who already have symptoms, tau is the major driver of disease [see Targeting Amyloid in Alzheimer’s Disease: No Longer Enough?]. They are looking to the tau pathway as a major target for potential anti-Alzheimer’s therapies.

“You could argue that it would be a perfect therapeutic target really, because it probably would prevent the symptoms of the disease from ever appearing,” says Goedert.

In the new study, Goedert and colleagues took brain extracts from P301S transgenic mice, whose brain cells make the mutant form of human tau found in inherited frontotemporal dementia and develop tangles as a result. After confirming that these extracts contained P301S tau, the researchers injected the material into the brains of ALZ17 mice, a transgenic strain that makes normal human forms of tau and ordinarily does not develop tangles.

The quantity of tangles injected was too small to be detected with a standard staining technique a day later, but 6, 12 and 15 months later, the ALZ17 mice showed abundant evidence of tangles. Tests showed that these tangles had been formed out of the mice’s own, human-type tau, not the mutant P301S tau, indicating that they had been induced (and that the mutant form didn’t just reproduce). The tau tangles also had spread to neighboring brain regions in a manner similar to the spread of tangles in people with Alzheimer’s disease.

In control experiments, neither ALZ17 mice injected with non-tau extracts nor those injected with brain extracts from ordinary “wild-type” mice showed any tau pathology. Moreover, when the researchers used antibodies to remove the P301S tau from the extracts, then injected them into the new mice, they found that this tau-free extract failed to induce tangles in the ALZ17 mice—thus strengthening the case that P301S tau was the active, tangle-inducing agent in the extracts.

More questions to answer

These results raise several issues. For example, the tangles induced in ALZ17 mice did not seem to cause brain damage or behavioral changes the way they do in people with Alzheimer’s and other tau-associated diseases, at least not during the 15 months after injection.

“What this means, at present, we don’t know,” says Goedert. But he adds that it may have to do with the inherent limitations of mouse models, including the fact that mouse brains on the whole seem much less prone to human neurodegenerative disease. Transgenic disease-model mice typically are designed to make (express) an unusually large number of copies of disease-causing genes, often pathologically mutated ones, and “if you don’t overexpress,” Goedert says, “you normally don’t get pathology within the lifespan of the mouse.”

A second key question is whether other forms of tau could also induce this infection-like spreading. Goedert and his colleagues are experimenting with injections of tangle-containing extracts from human brains with Alzheimer’s, as well as brain extracts from other tau-associated neurodegenerative diseases including Pick’s disease and progressive supranuclear palsy.

Neuroscientist Marc Diamond’s lab at the University of California, San Francisco, already has shown in laboratory experiments that tau can form into functionally distinct aggregates (clumps), thus perhaps accounting for the variety of diseases with which tau aggregates have been associated. In another study, published May 8 in the Journal of Biological Chemistry, the Diamond lab showed that aggregates of misfolded tau can be taken up by cells, causing internal tau to clump and then to be re-emitted to “infect” neighboring cells.

Both Diamond and Goedert suspect that this transmission mechanism is similar to that seen in prion diseases such as Creutzfeld-Jakob disease. But because tau aggregates are much less hardy than prions, they are unlikely to be as easily transmitted. However, the same misfolding and spreading process may apply to other neurodegenerative diseases, and not just those featuring prions or tau.

Parkinson’s disease and dementia with Lewy bodies, for example, have been associated with the spread of a misfolded protein called alpha-synuclein. While alpha-synuclein-expressing transgenic mice so far are “not as useful” as tau-expressing mice, Goedert says, he hopes soon to inject such mice with brain extracts from people with Parkinson’s disease to see if the extracts cause the spread of alpha-synuclein pathology. Other researchers already have shown that in cell transplant experiments in people with Parkinson’s, alpha-synuclein pathology seems to spread from the diseased host brain to the transplanted, previously healthy cells.

“I think this is going to be a very important area of research,” Diamond says, “because there are going to be more general [not just disease-specific] mechanisms that allow aggregates to move around and corrupt proteins, and if you can target these mechanisms, then potentially you could get silver bullets for neurodegenerative disease"