A password will be e-mailed to you.

Could Alzheimer’s Associated Amyloid Plaques Fight Bacterial Infections?

Summary: According to researchers, the expression of human amyloid beta protected against potentially lethal infections in mice, roundworms and cultured human brain cells.

Source: Mass General.

Human amyloid-beta acts as natural antibiotic in the brains of animal models.

A new study from Massachusetts General Hospital (MGH) investigators 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 body’s first-line defense against infection. Their study published in Science Translational Medicine finds that expression of human amyloid-beta (A-beta) was protective against potentially lethal infections in mice, in roundworms and in cultured human brain cells. The findings may lead to potential new therapeutic strategies and suggest limitations to therapies designed to eliminate 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,” says Robert Moir, MD, of the Genetics and Aging Research Unit in the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), 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.”

A 2010 study co-led by Moir and Rudolph Tanzi, PhD, director of the MGH-MIND Genetics and Aging unit and 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. A-beta from the brains of Alzheimer’s patients also suppressed the growth of cultured Candida yeast in that study, and subsequently other groups have documented synthetic A-beta’s action against influenza and herpes viruses.

The current study is the first to investigate the antimicrobial action of human A-beta in living models. The investigators first found 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. In fact, human A-beta expressed by living cells appears to be 1,000 times more potent against infection than does the synthetic A-beta used in previous studies.

That superiority appears to relate to properties of A-beta that have been 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. 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. The synthetic A-beta preparations used in earlier studies did not include oligomers; but in the current study, oligomeric human A-beta 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.

Tanzi explains, “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. 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.”

Image shows amyloid beta.

β-amyloid fibrils propagate from yeast surfaces and capture Candida albicans in culture medium. This material relates to a paper that appeared in the May 25, 2016, issue of Science Translational Medicine, published by AAAS. The paper, by D.K.V. Kumar at Massachusetts General Hospital in Charlestown, Mass., and colleagues was titled, “Amyloid-ß peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease.” NeuroscienceNews.com image is credited to D.K.V. Kumar et al. / Science Translational Medicine (2016).

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.”

Says Tanzi, “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.”

About this neurology research article

Moir is an assistant professor of Neurology at Harvard Medical School (HMS), and Tanzi is the Kennedy Professor of Neurology (Neuroscience) at HMS and vice-chair of Neurology at MGH. The co-lead authors of the Science Translational Medicine paper are Deepak K.V. Kumar, PhD, Se Hoon Choi, PhD, and Kevin Washicosky, of the MGH-MIND Genetics and Aging Unit. Additional co-authors are William A. Eimer, PhD, Stephanie Tucker, Jessica Ghofrani, and Aaron Lefkowitz, MGH-MIND; Gawain McColl, PhD, University of Melbourne, Australia, and Lee Goldstein, MD, Boston University.

Funding: This study was supported by National Institutes of Health grant 5R01 AI081990-02, the Cure Alzheimer’s Fund, and the Helmsley Charitable Trust.

Source: Terri Ogan – Mass General
Image Source: This NeuroscienceNews.com image is credited to D.K.V. Kumar et al. / Science Translational Medicine (2016).
Original Research: Abstract for “Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease” by Deepak Kumar Vijaya Kumar, Se Hoon Choi, Kevin J. Washicosky, William A. Eimer, Stephanie Tucker, Jessica Ghofrani1 Aaron Lefkowitz, Gawain McColl, Lee E. Goldstein, Rudolph E. Tanzi and Robert D. Moir in Science Translational Medicine. Published online May 25 2016 doi:10.1126/scitranslmed.aaf1059

Cite This NeuroscienceNews.com Article
Mass General. “Could Alzheimer’s Associated Amyloid Plaques Fight Bacterial Infections?.” NeuroscienceNews. NeuroscienceNews, 25 May 2016.
<http://neurosciencenews.com/amyloid-plaques-bacteria-4305/>.
Mass General. (2016, May 25). Could Alzheimer’s Associated Amyloid Plaques Fight Bacterial Infections?. NeuroscienceNews. Retrieved May 25, 2016 from http://neurosciencenews.com/amyloid-plaques-bacteria-4305/
Mass General. “Could Alzheimer’s Associated Amyloid Plaques Fight Bacterial Infections?.” http://neurosciencenews.com/amyloid-plaques-bacteria-4305/ (accessed May 25, 2016).

Abstract

Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease

The amyloid-β peptide (Aβ) is a key protein in Alzheimer’s disease (AD) pathology. We previously reported in vitro evidence suggesting that Aβ is an antimicrobial peptide. We present in vivo data showing that Aβ expression protects against fungal and bacterial infections in mouse, nematode, and cell culture models of AD. We show that Aβ oligomerization, a behavior traditionally viewed as intrinsically pathological, may be necessary for the antimicrobial activities of the peptide. Collectively, our data are consistent with a model in which soluble Aβ oligomers first bind to microbial cell wall carbohydrates via a heparin-binding domain. Developing protofibrils inhibited pathogen adhesion to host cells. Propagating β-amyloid fibrils mediate agglutination and eventual entrapment of unatttached microbes. Consistent with our model, Salmonella Typhimurium bacterial infection of the brains of transgenic 5XFAD mice resulted in rapid seeding and accelerated β-amyloid deposition, which closely colocalized with the invading bacteria. Our findings raise the intriguing possibility that β-amyloid may play a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis. These data suggest a dual protective/damaging role for Aβ, as has been described for other antimicrobial peptides.

“Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease” by Deepak Kumar Vijaya Kumar, Se Hoon Choi, Kevin J. Washicosky, William A. Eimer, Stephanie Tucker, Jessica Ghofrani1 Aaron Lefkowitz, Gawain McColl, Lee E. Goldstein, Rudolph E. Tanzi and Robert D. Moir in Science Translational Medicine. Published online May 25 2016 doi:10.1126/scitranslmed.aaf1059

Feel free to share this Neuroscience News.
Join our Newsletter
Sign up to receive the latest neuroscience headlines and summaries sent to your email daily from NeuroscienceNews.com
We hate spam. Your email address will not be sold or shared with anyone else.
No more articles