Alzheimer’s disease research and drug development has for the last several decades focused feircly on the elimination of amyloid-β — the protein that aggregates forming plaques in brain neurons of patients. Now, a new study suggests that the protein is part of the immune system, having an evolutionary important antimicrobial role in fighting invading pathogens by entrapping them in the sticky protein clusters.
“Neurodegeneration in Alzheimer’s disease has been thought to be caused by the abnormal behavior of amyloid-β molecules, which are known to gather into tough fibril-like structures called amyloid plaques within patients’ brains,” said senior study author Robert Moir of the Genetics and Aging Research Unit at Massachusetts General Hospital‘s Institute for Neurodegenerative Disease (MGH-MIND), said in a news release. “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.”
The presence and behavior of the amyloid-β protein has baffled researchers for ages, and the protein deposits associated to Alzheimer’s disease have been considered an accidental process caused by abnormal breakdown processes.
The researchers behind the recent findings published in Science Translational Medicine, had already flagged the possibility that the explanation was not good enough six years ago when they published a study demonstrating the ability of amyloid-β to function as an antimicrobial substance. Even earlier, Moir had noted that amyloid-β resembles a protein called LL-37, belonging to a class of factors known as antimicrobial peptides, which works to defend people against a host of different microbes.
The early study used a man-made form of amyloid-β, comparing its capacity to block the growth of various important pathogens to LL-37. They saw that amyloid-β was as effective, and sometimes even better than LL-37 in slowing microbial growth. The research team obtained the same results when using amyloid-β isolated from Alzheimer’s patient’s brains to block the growth of yeast — findings that were confirmed by other groups showing synthetic amyloid-β to prevent the spread of influenza and herpes viruses.
Since the old study was not performed in living animals, it did not highly impress the research society. For the new study, “Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease,” Moir, and his long-time colleague and co-author Rudolph E. Tanzi, revisited the phenomenon using mice, worms, and cultured human brain cells.
Using mice that produce human amyloid-β, researchers showed that when infected with brain salmonella, the amyloid-expressing mice survived longer than normal counterparts. The infected mice had extensive amyloid plaques that were seen to ensnare pathogens.
Also in a type of worm often used in research called C. elegans, an expression of human amyloid-β protected the worms from both salmonella and yeast infection. Work in cultured human brain cells revealed that amyloid-β was 1,000 times more potent in preventing infection that the synthetic version used in the older study.
Moir and Tanzi believe that the superiority is a result of the natural protein’s ability to form oligomers – aggregates of a few amyloid-β molecules that eventually accumulate into plaques. Other antimicrobial peptides use the method to trap pathogens, which form oligomers that bind to the surface of the invader and prevent it from interacting with human cells – eventually ensnaring the microbes in aggregates.
“Antimicrobial peptides 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 amyloid-β’s antimicrobial activities, has been implicated in several late-life diseases, including rheumatoid arthritis, lupus and atherosclerosis,” said Tanzi. “The sort of dysregulation of antimicrobial peptide activity that can cause sustained inflammation in those conditions could contribute to the neurodegenerative actions of amyloid-β in Alzheimer’s disease.”
The researchers believe it is impossible to know whether the reaction is a response to real infections or a dysregulated reaction to a false threat.
“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,” said Moir. “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.”
Still, according to Science News, others in the field are not convinced of the findings’ validity. The team now aims to take the models to humans.
Tanzi concluded: “While our data all involve experimental models, the important next step is to search for microbes in the brains of Alzheimer’s patients that may have triggered amyloid deposition as a protective response, later leading to nerve cell death and dementia. 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.”
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