Neurodegeneration in Alzheimer’s disease is thought to be caused by the abnormal behavior of amyloid-beta molecules, which are known to gather into tough fibril-like structures called amyloid plaques within patients’ brains. This widely held view has guided therapeutic strategies and drug development for more than 30 years. Now, a study from researchers at Massachusetts General Hospital (MGH) provides additional evidence that 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. The team state that their findings may lead to potential new therapeutic strategies and suggest limitations to therapies designed to eliminate amyloid plaques from patient’s brains. The study is published in the journal Science Translational Medicine.
Earlier studies from the lab showed that amyloid-beta had many of the qualities of an antimicrobial peptide (AMP), a small innate immune system protein that defends against pathogens. That study compared synthetic forms of amyloid-beta with a known AMP called LL-37 and found that amyloid-beta inhibited the growth of several important pathogens, sometimes as well or better than LL-37. Amyloid-beta from the brains of Alzheimer’s patients also suppressed the growth of cultured Candida yeast in that study, and subsequent groups documented synthetic amyloid-beta’s action against influenza and the herpes viruses. The current study is the first to investigate the antimicrobial action of human amyloid-beta in living models.
The current study shows that transgenic mice that express human amyloid-beta survived significantly longer after the induction of Salmonella infection in their brains than did mice with no genetic alteration. Results show that mice lacking the amyloid precursor protein died even more rapidly, and similarly, human amyloid-beta expression protected cultured neuronal cells from Candida. Data findings show that human amyloid-beta expressed by living cells appears to be 1,000 times more potent against infection than does the synthetic amyloid-beta used in previous studies.
The team explain that the superiority appears to relate to properties of amyloid-beta that are considered part of Alzheimer’s disease pathology, the propensity of small molecules to combine into what are called oligomers and then aggregate into beta-amyloid plaques. They go on to add that while AMPs fight infection through several mechanisms, a fundamental process involves forming oligomers that bind to microbial surfaces and then clump together into aggregates that both prevent the pathogens from attaching to host cells and allow the AMPs to kill microbes by disrupting their cellular membranes.
Results show that the synthetic amyloid-beta preparations used in earlier studies did not include oligomers, however, the oligomeric human amyloid-beta used here not only showed an even stronger antimicrobial activity, its aggregation into the sorts of fibrils that form beta-amyloid plaques was seen to entrap microbes in both mouse and roundworm models.
The team state that their 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. For the future, the researchers state that amyloid-based therapies aimed at dialing down and not wiping out beta-amyloid in the brain might be a better strategy when treating Alzheimer’s patients.
Michelle Petersen is the founder of Healthinnovations, having worked in the health and science industry for over 21 years, which includes tenure within the NHS and Oxford University. Healthinnovations is a publication that has reported on, influenced, and researched current and future innovations in health for the past decade.
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An avid campaigner in the fight against child sex abuse and trafficking, Michelle is a passionate humanist striving for a better quality of life for all humans by helping to provide traction for new technologies and techniques within healthcare.