Could Alzheimer’s stem from infections like Salmonella

Gina Kolata of The New York Times reports on new research by a team of investigators at Harvard which suggests Alzheimer’s disease stems from the toxic remnants of the brain’s attempt to fight off infection.

salm.alzIt is still early days, but Alzheimer’s experts not associated with the work are captivated by the idea that infections, including ones that are too mild to elicit symptoms, may produce a fierce reaction that leaves debris in the brain, causing Alzheimer’s. The idea is surprising, but it makes sense, and the Harvard group’s data, published Wednesday in the journal Science Translational Medicine, supports it. If it holds up, the hypothesis has major implications for preventing and treating this degenerative brain disease.

The Harvard researchers report a scenario seemingly out of science fiction. A virus, fungus or bacterium gets into the brain, passing through a membrane — the blood-brain barrier — that becomes leaky as people age. The brain’s defense system rushes in to stop the invader by making a sticky cage out of proteins, called beta amyloid. The microbe, like a fly in a spider web, becomes trapped in the cage and dies. What is left behind is the cage — a plaque that is the hallmark of Alzheimer’s.

So far, the group has confirmed this hypothesis in neurons growing in petri dishes as well as in yeast, roundworms, fruit flies and mice. There is much more work to be done to determine if a similar sequence happens in humans, but plans — and funding — are in place to start those studies, involving a multicenter project that will examine human brains.

“It’s interesting and provocative,” said Dr. Michael W. Weiner, a radiology professor at the University of California, San Francisco, and a principal investigator of the Alzheimer’s Disease Neuroimaging Initiative, a large national effort to track the progression of the disease and look for biomarkers like blood proteins and brain imaging to signal the disease’s presence.

The work began when Robert D. Moir, of Harvard Medical School and Massachusetts General Hospital, had an idea about the function of amyloid proteins, normal brain proteins whose role had long been a mystery.

The proteins were traditionally thought to be garbage that accumulates in the brain with age. But Dr. Moir noticed that they looked a lot like proteins of the innate immune system, a primitive system that is the body’s first line of defense against infections.

Elsewhere in the body, such proteins trap microbes — viruses, fungi, yeast and bacteria. Then white blood cells come by and clear up the mess. Perhaps amyloid was part of this system, Dr. Moir thought.

glen-campbell-ill-be-me-movie-reviewHe began collaborating with Rudolph E. Tanzi, also at Harvard Medical School and Massachusetts General Hospital, in a study funded by the National Institutes of Health and the Cure Alzheimer’s Fund. The idea was to see if amyloid trapped microbes in living animals and if mice without amyloid proteins were quickly ravaged by infections that amyloid could have stopped.

The answers, they reported, were yes and yes.

In one study, the group injected Salmonella bacteria into the brains of young mice that did not have plaques.

“Overnight, the bacteria seeded plaques,” Dr. Tanzi said. “The hippocampus was full of plaques, and each plaque had a single bacterium at its center.”

In contrast, mice that did not make beta amyloid succumbed more quickly to the bacterial infection, and did not make plaques.