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Human amyloid-beta acts as natural antibiotic in brains of animal models
06-07-2016
by Jeffrey Bouley  |  Email the author
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BOSTON—Late May brought news from Massachusetts General Hospital (MGH) that, interestingly, links Alzheimer’s disease and immunology, suggesting new therapeutic strategies for dealing with microbes.
 
In the study, MGH investigators provide evidence that the amyloid-beta protein, which is deposited in the form of beta-amyloid plaques in the brains of patients with Alzheimer’s disease, is a normal part of the innate immune system—that is to say, the first line of defense against infection in the body. Specifically, the results published in Science Translational Medicine find that expression of human amyloid-beta (A-beta) was protective against potentially lethal infections in two animal models—mice and roundworms—as well as in cultured human brain cells.
 
The findings may lead to potential new therapeutic strategies, they say, but also imply that there are limitations to therapies that are aimed at eliminating amyloid plaques from patient’s brains.
 
“Neurodegeneration in Alzheimer’s disease has been thought to be caused by the abnormal behavior of A-beta molecules, which are known to gather into tough fibril-like structures called amyloid plaques within patients’ brains,” said Dr. Robert Moir of the Genetics and Aging Research Unit in MGH’s Institute for Neurodegenerative Disease (MGH-MIND), who is co-corresponding author of the paper. “This widely held view has guided therapeutic strategies and drug development for more than 30 years, but our findings suggest that this view is incomplete.”
 
This current study isn’t the first hint of that. A 2010 study co-led by Moir and Dr. Rudolph Tanzi, who is director of the MGH-MIND Genetics and Aging Unit and a co-corresponding author of the current study, grew out of Moir’s observation that A-beta had many of the qualities of an antimicrobial peptide (AMP), a small innate immune system protein that defends against a wide range of pathogens. That study compared synthetic forms of A-beta with a known AMP called LL-37 and found that A-beta inhibited the growth of several important pathogens, sometimes as well or better than LL-37.
 
The earlier study suggested that A-beta from the brains of Alzheimer’s patients also suppressed the growth of cultured Candida yeast in that study. Other researchers have also demonstrated synthetic A-beta’s action against influenza and herpes viruses.
 
For example, a study published in February 2015 in Biogerontology about A-beta peptides displaying protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1 (HSV-1) in fibroblast, epithelial and neuronal cell lines noted that HSV-1 has been implicated as a risk factor for Alzheimer’s disease and found to co-localize within amyloid plaques, with the authors writing, “Overproduction of [A-beta] peptide to protect against latent herpes viruses, and eventually against other infections, may contribute to amyloid plaque formation, and partially explain why brain infections play a pathogenic role in the progression of the sporadic form of [Alzheimer’s disease].”
 
The current MGH study is reportedly the first to actually investigate antimicrobial action of human A-beta in living models, and they discovered that transgenic mice that express human A-beta survived significantly longer after the induction of Salmonella infection in their brains than did mice with no genetic alteration. Mice lacking the amyloid precursor protein died even more rapidly. Transgenic A-beta expression also appeared to protect C. elegans roundworms from either Candida or Salmonella infection. Similarly, human A-beta expression protected cultured neuronal cells from Candida.
 
Moreover, the study indicates that human A-beta expressed by living cells may be 1,000 times more potent against infection than the synthetic A-beta used in previous studies.
 
Certain properties of A-beta have been described as part of the pathology of Alzheimer’s disease—specifically the propensity of small molecules to combine into what are called oligomers and then aggregate into beta-amyloid plaques. The superior defense against infection seems to correlate to such properties. That is, while AMPs use many different methods to fight infection, a foundational process seems to involves forming oligomers that bind to microbial surfaces, clump together into aggregates and thus prevent the pathogens from attaching to host cells while the AMPs kill microbes by disrupting their cellular membranes.
 
The synthetic A-beta preparations used in earlier studies did not include oligomers.
 
“AMPs are known to play a role in the pathologies of a broad range of major and minor inflammatory disease; for example, LL-37, which has been our model for A-beta’s antimicrobial activities, has been implicated in several late-life diseases, including rheumatoid arthritis, lupus and atherosclerosis,” Tanzi explained. “The sort of dysregulation of AMP activity that can cause sustained inflammation in those conditions could contribute to the neurodegenerative actions of A-beta in Alzheimer’s disease.”
 
Moir adds, “Our findings raise the intriguing possibility that Alzheimer’s pathology may arise when the brain perceives itself to be under attack from invading pathogens, although further study will be required to determine whether or not a bona-fide infection is involved. It does appear likely that the inflammatory pathways of the innate immune system could be potential treatment targets. If validated, our data also warrant the need for caution with therapies aimed at totally removing beta-amyloid plaques. Amyloid-based therapies aimed at dialing down but not wiping out beta-amyloid in the brain might be a better strategy.”
 
A critical next step, said Tanzi, is to search for microbes in the brains of Alzheimer’s patients that may have triggered amyloid deposition as a protective response. These might be the responsible parties that lead to nerve cell death and dementia later on. “If we can identify the culprits—be they bacteria, viruses or yeast—we may be able to therapeutically target them for primary prevention of the disease.”
 
Code: E06081603

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