General consensus among Alzheimer’s researchers has it that the disease’s main culprit, a protein called amyloid beta, is an unfortunate waste product that is not known to play any useful role in the body—and one that can have devastating consequences. When not properly cleared from the brain it builds up into plaques that destroy synapses, the junctions between nerve cells, resulting in cognitive decline and memory loss. The protein has thus become a major drug target in the search for a cure to Alzheimer’s. 
 
 Now a team of researchers at Harvard Medical School and Massachusetts General Hospital are proposing a very different story. In a study published this week in Science Translational Medicine, neurologists Rudolph Tanzi and Robert Moir report evidence that amyloid beta serves a crucial purpose: protecting the brain from invading microbes. 
 
 “The original idea goes back to 2010 or so when Rob had a few too many Coronas,” Tanzi jokes. Moir had come across surprising similarities between amyloid beta and LL37, a protein that acts as a foot soldier in the brain’s innate immune system, killing potentially harmful bugs and alerting other cells to their presence. “These types of proteins, although small, are very sophisticated in what they do,” Moir says. “And they’re very ancient, going back to the dawn of multicellular life.” 
 
 Just as amyloid beta is known to do, these antimicrobial proteins can build up and form fibrils that, when not properly regulated, have harmful effects. Yet unlike amyloid beta, their role in the immune system has been widely accepted: They prevent microbes from adhering to host cells, and ultimately trap them. So five years ago the pair of researchers set out to determine whether amyloid beta could also act as a natural antibiotic. They had previously explored their hypothesis in vitro, but in this new study they used worms and mice. For these animal models they compared what happened when amyloid beta was overexpressed to when it was not produced, and found that the former led to increased resistance to infection and longer survival rates. 
 
 The team first infected cultured human and hamster cells with a type of fungus called Candida albicans and found that high expression of amyloid beta had a protective effect, doubling the number of cells that were not infected. The researchers then moved on to roundworms, or nematodes, which usually do not survive for more than two to three days once the fungus takes hold. The nematodes with overexpressed amyloid beta, however, were still going strong five to six days after they were infected. Finally, the researchers infected the brains of mice with a strain of salmonella to cause meningitis. Mice that were genetically altered to overproduce human amyloid beta survived nearly twice as long as mice that did not have the protein at all. 
 
 Most shocking of all, according to Tanzi and Moir, was that when they injected bacteria into the brains of Alzheimer’s mouse models, amyloid plaques—the hallmark of the disease—formed within 48 hours. “We didn’t know this was even possible,” Tanzi says, “that amyloid plaques would form rapidly overnight.” And in the middle of each plaque was one Salmonella bacterium, supporting the theory that the amyloid deposition had formed around the microbe as an entrapment mechanism—just like LL37 and other established antimicrobial proteins. 
 
 “These results are particularly intriguing,” says Anna Palamara, a microbiologist at the Sapienza University of Rome who was not involved in the study. “Previous [research] shows that several infectious agents, including viruses, trigger amyloid beta production and accumulation.” Herpes and influenza are just two of the infections that have been tested by other research teams. 
 
 The Harvard team’s new findings provide further evidence that Alzheimer’s could be inadvertently spurred by an infection that causes the formation of too much amyloid. As people get older the immune system and blood-brain barrier become increasingly compromised, making it easier for microbes to sneak into the brain. It wouldn’t take many of these pathogens, according to Tanzi, to cause amyloid buildup. “And that could rapidly start the cascade toward the disease,” he says, “causing tangles and inflammation. You’ve got all three pillars of Alzheimer’s right there.” 
 
 “It is possible to speculate that during a mild infection the production of amyloid beta may help,” Palamara says. “But in the presence of persistent or repeated infections, amyloid beta levels may accumulate, exceeding a threshold. In this case its protective role might change to the well-known neurotoxic one.” 
 
 The idea that amyloid beta has a positive function in the body could potentially change how scientists approach potential treatments. Instead of attempting to completely eliminate the protein, “we might want to think about just dialing it down,” Tanzi says. Moreover, Moir adds, the drugs in trials now are for the most part designed to reduce inflammation by targeting pathways in the adaptive immune system. But if amyloid production and deposition are innate immune responses, then targeting pathways of innate immunity or the microbes themselves may be the way to go. 
 
 They do not expect convincing the scientific community of this to be easy. “This is really going to cause a lot of unrest in the field,” Tanzi says. “Any new revolutionary discovery is first ridiculed, then violently opposed, and finally taken to be self-evident. We’re ready for the ridicule and the violent opposition, and we think we have enough data so that we can look forward to self-evident.” 
 
 But the pair has a long way to go. They are now moving forward with a plan to systematically characterize the microbes found in the aging brain. From there they hope to identify the pathogens that may be involved in the onset of Alzheimer’s—as well as those that potentially play a role in other amyloid diseases, such as diabetes. 
 
 “We’re at the top of a mountain with a freshly formed layer of snow,” Moir says. “Where you go is where you choose. There’s so much to explore.” 

 Juan Gaertner/Science Photo Library 
 
 It’s a double-edged sword. The protein plaques in the brain associated with Alzheimer’s disease could be created as our immune system fights off invading microbes. 
 
 Alzheimer’s disease has long been linked to the accumulation of sticky plaques of beta-amyloid proteins in the brain, but their function – if any – has remained unclear. 
 
 “Why does beta-amyloid accumulate in people as they get older? Does it play a role in the brain, or is it just garbage that accumulates,” asks Rudolph Tanzi of Harvard Medical School. 
 
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 Tanzi’s team has been working with Robert Moir at the Massachusetts General Hospital in Boston to look at the protein in other animals. The group has found that a certain sequence of particular amino acids in human beta-amyloid is shared widely – among 70 per cent of vertebrates, including in the coelacanth, an ancient type of fish. 
 
 That this sequence is shared so widely, and has not changed over time, suggests there is a reason it has been conserved. “This is a very old peptide doing something that’s important,” says Moir. 
 
 Brain defence 
 
 Moir had previously found that beta-amyloid kills microbes as well as does an anti-microbial peptide called LL-37. This molecule is a foot soldier for the primitive part of our immune system, which we share with many other animals. 
 
 So the team tested whether the purpose of beta-amyloid is also to kill microbes in the brain. When they injected bacteria into the brains of mice bred to be able to develop plaques much as humans do, the mice developed amyloid plaques overnight. 
 
 “When you look in the plaques, each one had a single bacterium in it,” says Tanzi. “A single bacterium can induce an entire plaque overnight.” 
 
 This suggests that microbial infection could be triggering the formation of plaques that cause Alzheimer’s disease. Somehow, bacteria, viruses or other pathogens may be crossing the blood-brain barrier and getting into the brain. The brain may be responding by using beta-amyloid to trap and kill them. But if these plaques aren’t cleared away fast enough, they may then lead to inflammation and tangles of another protein, called tau, causing neurons to die and the progression towards Alzheimer’s disease. 
 
 “The stickiness of amyloid is both a godsend and a curse,” says Samuel Gandy at the Mount Sinai Hospital in New York. 
 
 Alzheimer’s vaccination 
 
 Other work has suggested that infections can cause Alzheimer’s disease, arguing that microbes lead to inflammation, directly causing neuron death and cognitive decline. Chlamydia and the herpes virus are among the suggested culprits. 
 
 But Tanzi and Moir believe it is beta-amyloid that causes the damage, not the microbes themselves. 
 
 The team now plans to look at the brains of people who have died from Alzheimer’s disease. If the team finds microbial DNA or RNA inside the plaques, the discovery could open up a new way to think about Alzheimer’s disease and how it might be treated. 
 
 “You could vaccinate against those pathogens, and potentially prevent this problem arising later in life,” says Moir. 
 
 Journal reference: Science Translational Medicine, DOI: 10.1126/scitranslmed.aaf1059 
 
 Read more: Universal plaque-busting drug could treat various brain diseases
– A new study out of Harvard puts forward what the New York Times calls a "startling hypothesis" about Alzheimer's. The research published in Science Translational Medicine suggests that old infections in the brain—or, more specifically, the body's attempt to fight them off—may be at the root of the disease. The study revolves around the telltale plaque in the brain associated with Alzheimer's, which is caused by a buildup of a protein called amyloid beta. Scientists have never been sure why the protein begins to build up as people age. “Does it play a role in the brain, or is it just garbage that accumulates?" is how Harvard's Rudolph Tanzi frames the question per New Scientist. His study suggests that it does indeed play a role, and an important one: The body produces the protein to fight off infections that pass into the brain through the blood-brain barrier; the problem occurs when it doesn't get properly cleared away after the fight. “It’s interesting and provocative,” an Alzheimer's researcher at the University of California, San Francisco, tells the Times of theory. It's been tested on mice and roundworms but not humans yet. "Most shocking of all," writes Scientific American, "was that when they injected bacteria into the brains of Alzheimer’s mouse models, amyloid plaques—the hallmark of the disease—formed within 48 hours." If further research backs up the notion, it could lead to new ways of treating the disease. For example, if this protein that eventually causes trouble comes into being originally as a way to fight pathogens, "you could vaccinate against those pathogens, and potentially prevent this problem arising later in life,” says Tanzi's co-author, Robert Moir of Massachusetts General Hospital. (Maybe memories lost to Alzheimer's aren't gone forever?)