Alzheimer’s culprit may fight other diseases

A notorious Alzheimer’s disease villain may also be a germ-busting superhero. Amyloid-beta gums up the brains of people with Alzheimer’s but also takes out dangerous brain invaders, scientists report May 25 in Science Translational Medicine.

As strong as steel, tough strands of A-beta protein imprison pathogens that threaten the body and brain, experiments in mice and worms show. Those results raise the possibility that A-beta plays a role in the immune system and its accumulation in Alzheimer’s might be prompted by an infection.
Earlier studies have shown that A-beta can bust germs in cells in dishes, but the new experiment shows A-beta protection in living mice and worms. Mice engineered to have the human form of A-beta better survived a brain infection of Salmonella bacteria than mice without the human A-beta, Robert Moir and Rudolph Tanzi, both of Harvard Medical School, and colleagues found. And in the bodies of worms, A-beta helped stave off the dangerous yeast Candida.

When researchers injected Salmonella into mice’s hippocampi, a brain area damaged in Alzheimer’s, A-beta quickly sprang into action. It swarmed the bugs and formed aggregates called fibrils and plaques. “Overnight you see the plaques throughout the hippocampus where the bugs were, and then in each single plaque is a single bacterium,” Tanzi says. That rapid response was surprising, he says. “No one expected that.”
And those prisons are probably permanent, Moir says. “In A-beta, those fibrils set like concrete and the bugs have no chance of ever getting out.”

Alzheimer’s has been linked to a host of bacterial, fungal and viral infections, says immunologist Kevan Hartshorn of Boston University School of Medicine. That work, along with the new study, raises the possibility that Alzheimer’s could be spurred by an immune response to a pathogen.

That’s “an extremely provocative and interesting hypothesis,” says neuroscientist Berislav Zlokovic of the University of Southern California in Los Angeles, who says the new data are convincing. But it remains to be seen whether the results are relevant for people with Alzheimer’s. Zlokovic and colleagues recently found that the barrier between brain and blood weakens with age — a situation that could let more microbes into the brain and perhaps spur A-beta accumulation.
A-beta appears to be a general immune system fighter that’s effective against many enemies, says Moir. “This is a classical innate immune response, which means that whatever gets thrown at it, it does the same thing,” he says. “So whether it’s a herpesvirus, a spirochete or chlamydia, it’s going to generate A-beta plaques.”

Moir also raises the possibility that the amyloid’s germ-busting job might play a role in other diseases that come with amyloid accumulation, such as diabetes or heart disease. “I think we may have stumbled across an underlying theme in a lot of major diseases,” he says.

Finding this helpful role for A-beta may complicate a therapeutic approach for Alzheimer’s that attempts to reduce levels of the protein with antibodies, says molecular pharmacologist Marina Ziche of the University of Siena in Italy. “I have always been very skeptical about that approach,” and the new results suggest that people benefit from some A-beta, Ziche says.

The next step is to see whether pathogens are entombed in A-beta plaques in the human brain, Tanzi says. “Now it’s time to start looking for them in patients.” To start, he and colleagues have just begun a project to catalog the collection of microbes in healthy brains and brains with Alzheimer’s.

Finding a strong link between pathogens and Alzheimer’s could suggest new ways to prevent the disease, Tanzi says. Vaccines that fight infections, for instance, might be one way to prevent A-beta pileup.