Human amyloid-beta acts as natural antibiotic in the brains of animal modelsMay 25, 2016
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."
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."
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals, earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service and returned to the number one spot on the 2015-16 U.S. News & World Report list of "America's Best Hospitals."
Massachusetts General Hospital
Related Microbes Articles:
Duke researchers have shown that microbes can control their animal hosts by manipulating the molecular machinery of their cells, triggering patterns of gene expression that consequently contribute to health and disease.
What looks like a caterpillar chewing on a leaf or a beetle consuming fruit is likely a three-way battle that benefits most, if not all of the players involved, according to a Penn State entomologist.
In the microbial world, vitamin B12 is a hot commodity.
University of Utah researchers will be among the scientists convening in New Orleans for the 2017 Annual Meeting for the Society for Integrative and Comparative Biology Jan.
New research in mice may in the future help dieters keep the weight off.
A research team at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg has taken an important step in modelling the complexity of the human gut's bacterial communities -- the microbiome -- on the computer.
Two bacterial species that inhabit the human gut activate immune cells to boost the effectiveness of a commonly prescribed anticancer drug, researchers report Oct.
Microbes improve soil quality by cycling nutrients and breaking plant residues down into soil organic matter.
Plants can better tolerate drought and other stressors with the help of natural microbes, University of Washington research has found.
Scientists have tried to alter the human gut microbiota to improve health by introducing beneficial probiotic bacteria.
Related Microbes Reading:
Teaming with Microbes: The Organic Gardener's Guide to the Soil Food Web, Revised Edition
by Jeff Lowenfels (Author), Wayne Lewis (Author)
The 2011 Garden Writers of America Gold Award for Best Writing/Book proves soil is anything but an inert substance. Healthy soil is teeming with life -- not just earthworms and insects, but a staggering multitude of bacteria, fungi, and other microorganisms. When we use chemical fertilizers, we injure the microbial life that sustains healthy plants, and thus become increasingly dependent on an arsenal of artificial substances, many of them toxic to humans as well as other forms of life. But there is an alternative to this vicious circle: to garden in a way that strengthens, rather than... View Details
I Contain Multitudes: The Microbes Within Us and a Grander View of Life
by Ed Yong (Author)
New York Times Bestseller
New York Times Notable Book of 2016
NPR Great Read of 2016
Economist Best Books of 2016
Brain Pickings Best Science Books of 2016
Smithsonian Best Books about Science of 2016
Science Friday Best Science Book of 2016
A Mother Jones Notable Read of 2016
A Bill Gates “Gates Notes” Pick
MPR Best Books of... View Details Brings the excitement, breadth, and power of the modern microbial sciences to the next generation of students and scientists. This new edition of Microbe is an eloquent and highly readable introduction to microbiology that will engage and excite science majors and pre-health professionals. The authors, all prominent scientists, have carefully crafted this lively narrative to bring key microbiology concepts to life and promote a lifelong passion for the microbial sciences. Far more than a comprehensive reference book, Microbe is replete with case... View Details You are just 10% human. For every one of the cells that make up the vessel that you call your body, there are nine impostor cells hitching a ride. You are not just flesh and blood, muscle and bone, brain and skin, but also bacteria and fungi. Over your lifetime, you will carry the equivalent weight of five African elephants in microbes. You are not an individual but a colony. Until recently, we had thought our microbes hardly mattered, but science is revealing a different story, one in which microbes run our bodies; remaining a healthy human is impossible without them. This science classic by Paul de Kruif chronicles the pioneering bacteriological work of the first scientists to see and learn from the microscopic world. Paul de Kruif's Microbe Hunters is a timeless dramatization of the scientists, bacteriologists, doctors, and medical technicians who discovered microbes and invented the vaccines to counter them. De Kruif reveals the now seemingly simple but really fundamental discoveries of science—for instance, how a microbe was first viewed in a clear drop of rain water, and when, for the first time ever, Louis Pasteur... View Details
Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues
by Martin J. Blaser MD (Author)
"A critically important and startling look at the harmful effects of overusing antibiotics, from the field's leading expert Tracing one scientist's journey toward understanding the crucial importance of the microbiome, this revolutionary book will take readers to the forefront of trail-blazing research while revealing the damage that overuse of antibiotics is doing to our health: contributing to the rise of obesity, asthma, diabetes, and certain forms of cancer. In Missing Microbes, Dr. Martin Blaser invites us into the wilds of the human microbiome where for hundreds of thousands of years... View Details
Tiny Creatures: The World of Microbes (Read and Wonder)
by Nicola Davies (Author), Emily Sutton (Illustrator)
"Sutton's large-scale illustrations help children to visualize microorganisms and processes that are too small to see. . . . A handsome and rewarding picture book." — Booklist (starred review) All around the world—in the sea, in the soil, in the air, and in your body—there are living things so tiny that millions could fit on an ant's antenna. They're busy doing all sorts of things, from giving you a cold and making yogurt to eroding mountains and helping to make the air we breathe. View Details
by Michele Swanson (Author), Gemma Reguera (Author), Moselio Schaechter (Author), Frederick C. Neidhardt (Author)
Planet of Microbes: The Perils and Potential of Earth's Essential Life Forms
by Ted Anton (Author)
We live in a time of unprecedented scientific knowledge about the origins of life on Earth. But if we want to grasp the big picture, we have to start small—very small. That’s because the real heroes of the story of life on Earth are microbes, the tiny living organisms we cannot see with the naked eye. Microbes were Earth’s first lifeforms, early anaerobic inhabitants that created the air we breathe. Today they live, invisible and seemingly invincible, in every corner of the planet, from Yellowstone’s scalding hot springs to Antarctic mountaintops to inside our very bodies—more than... View Details
Pasteur's Fight Against Microbes (Science Stories)
by Beverly Birch (Author), Christian Birmingham (Author)
n 1856, when Louis Pasteur first began studying microbes in rotten sugarbeet juice, he put into motion a chain of events that saved France's wine industry, and revolutionized medicine and biology. View Details
10% Human: How Your Body's Microbes Hold the Key to Health and Happiness
by Alanna Collen (Author)
by Moselio Schaechter (Author), John L. Ingraham (Author), Frederick C. Neidhardt (Author)
An exciting introduction to the world of microbes
• Covers the most pertinent information related to the study of microbes, including microbial activity; structure and function; growth, inheritance, physiology, and diversity; and biological interactions
• Engages students in the learning process with a clear style and unique perspective
• Serves as a textbook for upper level undergraduate courses in general microbiology. View Details
Brings the excitement, breadth, and power of the modern microbial sciences to the next generation of students and scientists.
This new edition of Microbe is an eloquent and highly readable introduction to microbiology that will engage and excite science majors and pre-health professionals. The authors, all prominent scientists, have carefully crafted this lively narrative to bring key microbiology concepts to life and promote a lifelong passion for the microbial sciences.
Far more than a comprehensive reference book, Microbe is replete with case... View Details
You are just 10% human. For every one of the cells that make up the vessel that you call your body, there are nine impostor cells hitching a ride. You are not just flesh and blood, muscle and bone, brain and skin, but also bacteria and fungi. Over your lifetime, you will carry the equivalent weight of five African elephants in microbes. You are not an individual but a colony.
Until recently, we had thought our microbes hardly mattered, but science is revealing a different story, one in which microbes run our bodies; remaining a healthy human is impossible without them.
This science classic by Paul de Kruif chronicles the pioneering bacteriological work of the first scientists to see and learn from the microscopic world.
Paul de Kruif's Microbe Hunters is a timeless dramatization of the scientists, bacteriologists, doctors, and medical technicians who discovered microbes and invented the vaccines to counter them. De Kruif reveals the now seemingly simple but really fundamental discoveries of science—for instance, how a microbe was first viewed in a clear drop of rain water, and when, for the first time ever, Louis Pasteur... View Details