Contagion Spreads By Many Vectors
By Jim Schnabel, October 22, 2010
Tiny clusters of amyloid-beta (A-beta), long believed to trigger Alzheimer’s disease, are “infectious” enough that they can spread into the brain from the body, according to a new study that appeared online in Science on Oct. 21. The finding suggests that in principle, Alzheimer’s could spread like an infectious disease—although in practice, it is probably far too weakly infectious ever to do so. The study’s main significance is that it highlights and strengthens a new theory for the origin of many neurodegenerative diseases: the proliferation and spread of sticky clusters of proteins that somehow evade the brain’s cleanup mechanisms and trigger the deaths of neurons.
“We are working on understanding the mechanism and trying to do the same experiments with other protein aggregates,” says Mathias Jucker, a professor of cellular neurology at the University of Tübingen in Germany, and senior author of the study.
Most proteins in our bodies harbor small segments with a peculiar self-complementary stickiness, which enables two copies of such a segment to bind very tightly together. These self-sticky segments may reflect a primordial self-assembling capacity that a typical protein no longer needs. Whatever their origin, most such segments now are safely hidden or inaccessible amid the complex folds of their host proteins. A few proteins, however, have relatively simple and unstable structures, and thus appear to require very little deformation before their self-sticky segments become sufficiently exposed. When this deformation occurs, for example due to encounters with reactive oxygen molecules during periods of inflammation or cellular stress, the sticky segments can start to bind to their counterparts on other copies of the same protein.
It appears that when two or more copies of a protein have bound together in this way, they start to deform even normal copies of that protein, causing them to join the growing cluster. Eventually, the cluster turns into a long, insoluble stack of these corrupted proteins, and often wraps around other such stacks. Under a microscope, these stacks have a fibrous, thread-like appearance, and are known as amyloid fibrils. As the stacks lengthen, they eventually break into smaller pieces; they may also be cut into small segments by cleanup processes within cells. Each of these small pieces can then seed the growth of a new fibril.
Amyloid fibrils are found in people with Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Creutzfeldt-Jakob disease, type 2 diabetes, and a host of other diseases, many of them involving the degeneration of neurons. The proteins that form amyloid fibrils in these diseases include A-beta, tau, alpha-synuclein, and prion protein.
In the past several years, researchers have been trying to zero in on the most toxic, disease-related clusters involved in this process (see “Amyloid-Beta ‘Oligomers’ May Be Link to Alzheimer’s Dementia”). But they also have been uncovering evidence that this entire process, with all its byproducts, can spread in an infection-like manner—and not just for the notorious prion diseases, which were first discovered among brain-eating cannibal tribes in New Guinea.
In 2008, for example, researchers reported that alpha-synuclein aggregates had spread from Parkinson’s disease-affected brain tissue into more youthful transplanted brain cells. The following year brought evidence that clusters of tau proteins, which have long been implicated in the later stages of Alzheimer’s, could spread from outside cells into cellular interiors, and could even proliferate when injected into the brains of mice. (See “Researchers Eye Role of ‘Infectious’ Proteins in Neurodegenerative Disease”.)
There also has been evidence that clusters of A-beta, widely considered the likely triggers of Alzheimer’s, can spread infectiously. Jucker and his colleagues reported in 2006 that they could create amyloid deposits in the brains and cerebral blood vessels of mice by injecting, into their brains, diseased neural tissues from Alzheimer’s patients or from aged mice with Alzheimer’s-like A-beta deposits—and that anti-A-beta antibodies could block this transmission.
In the new study, the researchers showed that they could transmit this Alzheimer’s-like condition merely by injecting A-beta-containing brain material from aged “Alzheimer’s mice” into the bodies of much younger and healthier mice. By comparison with a direct brain injection, this method took months longer—about seven months in all—to effectively transmit the “amyloidosis” condition, and also required 1,000 times the volume of injected brain material.
This body-to-brain spread isn’t likely to be occurring in actual cases of Alzheimer’s. But it shows in a striking way that disease-linked forms of A-beta can spread like prions, if much less efficiently. Marc Diamond, a neurologist at the University of Washington at St. Louis who has done much-cited work in this area, calls the study “a proof of concept that an amyloid protein other than prion protein can get into the brain from the periphery.”
“I think it should concern laboratory personnel who handle fresh brain material, and in particular people like us who try to isolate, concentrate and analyze A-beta from the brain,” says Jucker. “We have made a significant investment in increasing safety precautions in our lab.”
Further work will be required to determine precisely how A-beta clusters can cross from the body into the brain. Diamond suggests that the first stop, as for infectious prions, might be in amyloid-devouring cells of the immune system. Jucker hints that A-beta is carried by such cells across the blood-brain barrier in cerebral vessels: “My guess,” he says, “is that it crosses via the blood and cellular blood components.”