Could it be that Alzheimer’s disease stems from the toxic remnants of the brain’s attempt to fight off infection?
Provocative new research by a team of investigators at Harvard leads to this startling hypothesis, which could explain the origins of plaque — the mysterious hard little balls that pockmark the brain of people with Alzheimer’s.
It is still early, but Alzheimer’s experts are captivated by the idea that infections, including ones that are to o 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 is the cage aplaque 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 multi center project that will examine human brains.
“It’s interesting; and provocative,” said Dr. Michael Weiner, a professor at the University of California, San Francisco, and a principal investigator of the Alzheimer’s Disease Neuro imaging Initiative, a large national effort to track the progression of the disease and look for biomarkers to signal the disease’s presence.
The work began when Robert Moir, of Harvard Medical School and Massachusetts General Hospital, had an idea about the function of amyloid proteins normal brain proteins whose role had been a mystery. The proteins were thought to be garbage that accumulates in the brain with age. But Moir noticed that they looked a lot like proteins of the innate immune system.
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, Moir thought.
He began collaborating with Rudolph 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. “Overnight, the bacteria seeded plaques,” Tanzi said “The hippocampus was full of plaques.”
In contrast, mice that did not make beta amyloid succumbed more quickly to the bacterial infection, and did not make plaques.
Dt Berislav Zlokovicem, director of the Zilkha Neurogenetic Institute at the University of Southern California, said his studies of the blood brain barrier also fit well with the new hypothesis. When he discovered that the barrier started to break down with aging, he noticed that the leakiest part was the membrane that protects the hippo campus, the site of learning and memory That is also where Alzheimer’s plaques form.
Tanzi and Moir’s hypothesis, he said “is very hypothetical at this point, but it does make sense.”