ARTICLE IN BRIEF
Investigators report that amyloid beta can act as an antimicrobial peptide and may play a role as an effector molecule of innate immunity.
Investigators at Harvard Medical School have discovered that amyloid beta (Abeta), the protein that accumulates in the classic hallmark of Alzheimer disease (AD) plaques, resembles a peptide that can act as an antimicrobial peptide and may play a role as an effector molecule of innate immunity.
The findings may have implications for the development of Alzheimer disease therapies, suggested Robert D. Moir, PhD, and colleagues in the paper published March 3 online in the open-access journal, PLoS ONE.
“The similarities between Abeta and antimicrobials had been staring us in the face for decades,” study author Rudolph E. Tanzi, PhD, the Joseph P. and Rose F. Kennedy Professor of Neurology, told Neurology Today in a telephone interview. “Abeta looks in size, structure, and biochemical properties like an antimicrobial peptide [called LL-37]. In fact, we have shown that it is a bonafide antimicrobial peptide.”
In in vitro assays, the scientists tested the antimicrobial activity of both Abeta and LL-37 against eight common microorganisms, including streptococcus, staphylococcus aureus, and listeria. When Abeta worked as well against the infectious agents — and sometimes better — than LL-37, they went the next step to see whether brain tissue from AD patients and age-matched non-AD patients would also fend off pathogens in vitro.
The scientists observed significantly higher antimicrobial activity in the tissue from the AD brains than non-AD brains. A third study was conducted to block Abeta activity and they found a significant reduction in antimicrobial activity.
“It was a real surprise to us,” said Dr. Tanzi, who has been studying the genetics of AD for decades. Based on this mounting evidence, Dr. Tanzi said he is convinced that Abeta is triggered by the body's innate immune system to help clear away infections. Abeta, he said, “is the brain's protector.”
He said it is like an autoimmune disease without antibody. The antimicrobial peptide, regulated by the innate immune system, turns against the body.
“When the brain needs to protect itself Abeta gets turned up,” he explained. It can happen on the heels of infection or in response to stroke or traumatic brain injury. “This means we have a whole new way to look at, and treat, Alzheimer disease,” he said.
“Chronic low grade infections or injury triggers Abeta to mount an immune response,” Dr. Tanzi speculated. “But if you have too robust a response or have too many brain insults it adds up to AD. This explains why Abeta (and AD) go up with age.”
IMPLICATIONS OF FINDINGS
The finding also calls into question whether or not the generation of drugs now being tested to get rid of Abeta may have negative consequences in reducing the body's innate immune response to infections.
Dr. Tanzi said the results also help explain why people who carry one or two copies of apolipoprotein E 4 (APOE4), which leads to higher Abeta levels in the brain, puts people at higher risk for infections and cardiovascular diseases. Similarly, the antimicrobial LL-37 has also been associated with pathology of several non-infectious diseases, including plaques in atherosclerosis.
How the evolutionary advantages and disadvantages of APOE4 play out is complex since Abeta protein appears to play a role in a number of common diseases. Carrying a copy of the APOE4 allele has been shown to predispose carriers to increased rates of CNS infection, probably by facilitating passage of pathogens across the blood-brain-barrier. It is a risk factor for AD and seems to be protective against diabetic nephropathy. APOE4 is also a risk factor for cardiovascular disease.
Given the complexity of the interactions of the APOE4 allele, Dr. Moir said that he “doesn't think the survival of the E4 genotype in the human population can be used to support any simple hypothesis against, or for, Abeta antimicrobial activity.
Dr. Moir and his colleagues propose that CNS infections would initiate an increase in Abeta levels as part of the defense response of the innate immune system. If amyloid is part of the antimicrobial mechanism of Abeta, fibrillar material would also be expected to accumulate as long as the innate immune system (correctly or incorrectly) perceives an infection.
Dr. Moir said that they suspect that suppression of Abeta may have the unintended consequence of suppressing innate immunity. Data from at least two studies support this. The first was the observation that genetically modified mice that lack the proteases needed to generate Abeta have a 60 percent neonate mortality unless raised in sterile conditions. Notably, four major markers of adaptive immune function were normal in these mice. The second finding comes from a clinical study of the drug tarenflurbil, published in 2009 in the Journal of the American Medical Association that was shown to slightly lower Abeta production. A side effect of patients taking tarenflurbil is significantly increased rates of infection.
“If we can figure out the common triggers with age we may be able to prevent the production of too much amyloid,” Dr. Tanzi said. “We have to know how to dial it down like we do with [using statins] to control cholesterol.”
“This is paradigm shifting,” added Dr. Tanzi. “Our finding says that Abeta has a purpose. These results have completely changed my view of Alzheimer disease.”
Other investigators have pointed to brain infections and the increased risk for AD. Brian Balin, PhD, professor of pathology and director of the Center for Chronic Disorders of Aging at the Philadelphia College of Osteopathic Medicine, said: “We are excited that someone is thinking out of the box in ways that others haven't considered. Most of the evidence about infections and AD has been ignored. The Harvard researchers are going about this in a rational way.”
“It's not such a radical idea,” he added. “HIV can trigger dementia. Why not other organisms?”
“The unanswered question pertains to the importance of Abeta as an antimicrobial in vivo,” said Samuel E. Gandy, MD, PhD, Mount Sinai Professor of Alzheimer's Disease Research, professor of neurology and psychiatry, and associate director of the Mount Sinai Alzheimer's Disease Research Center.
“A simple way to test this would be to look at APP [amyloid precursor protein] overexpressing mice to see whether the titer of the inoculum required to cause encephalomyelitis was modified according to the APP overdose. If amyloid beta is an antimicroblial in vivo, then it should take more pathogens to infect an APP-overexpressing mouse than it does to infect a wildtype mouse. I would like to see some live animal data before I tried to estimate the relevance in humans.”
The Harvard group is now doing these experiments. The strength of the recent findings led to federal funding to continue the work, Dr. Moir said.
“It is a very clever idea,” said Norman Relkin, MD, PhD, associate professor of clinical neurology and neuroscience at Weill Cornell Medical College and director of the Cornell Memory Disorders Program. “I am an advocate of the idea that the innate immune system plays a role in Alzheimer disease. Like all good ideas it will generate new ideas and new thinking.”
But, he added, the “finding has to be reconciled with everything we know about Abeta. The protein is toxic to brain cells.” He said that Abeta is the most rapidly turned over peptide in the body. “It doesn't sound like the way the body would regulate an immune response. I don't feel that the brain would use something against infection that is so toxic to brain cells.”
Dr. Tanzi added that antimicrobial peptides are cleared from the brain very quickly and there is evidence that in large amounts they can be toxic to brain cells too.