Published on: July 26, 2018
by Robin Seaton Jefferson for Forbes:
In the end it will be microbes—bacteria, viruses and fungus—found to be at the root of all disease and aging, and specifically Alzheimer’s, contends geneticist Dr. Rudolph “Rudy” Emile Tanzi.
“The two biggest threats to healthy aging have had to do with dealing with infection,” said Tanzi, who specializes in Alzheimer’s and the brain at Massachusetts General Hospital (MGH) and Harvard Medical School. “Think about it. When we increased the lifespan from 35 to 50, it was by covering the sewers. When we increased the lifespan from 50 to 75, it was with the use of antibiotics. Now we are looking for viruses in all of the major life-threatening diseases of our time—Alzheimer’s, cancer, Parkinson’s—and guess what? Infection is now cropping up in all of them.”
And though evidence continues to mount that could prove his theory, Tanzi says scientists are just beginning to scratch the surface of the culprits that can trigger the spiral into Alzheimer’s disease.
It’s one of the reasons scientists in Tanzi’s lab at MGH are mapping the microbiome of the brain—the population of microorganisms, some helpful and some pathological, that exists inside the brain—utilizing autopsied brain samples that tested positive for Alzheimer’s disease pathology. Researchers with The Brain Microbiome Project are looking for the most common germs found in the brain to attempt to determine which ones ultimately lead to Alzheimer’s disease. With the information, they hope to develop therapeutics for preventing and treating the disease that is projected to destroy the brains of nearly 14 million Americans by 2050.
Tanzi, Robert Moir and their team of Harvard researchers found more evidence this month to support the belief that microbes are indeed at the heart of Alzheimer’s disease. The team reported in the journal Neuron findings that suggest herpes viruses can set off the cascade of events that leads to Alzheimer’s disease.
In separate experiments, researchers studied how neurons in mice responded to the presence of herpes simplex 1 (HSV-1), the virus that causes cold sores and herpes virus 6 (HHV-6), the virus that causes the childhood skin disease roseola. (Most people catch these viruses early in life, and typically, they remain dormant. However, as we age, they almost always migrate up to the brain.)
In these experiments, scientists genetically bred some of the mice to have neurons that could create the human version of a protein called amyloid beta. Normally produced in the brain, amyloid beta is thought to be responsible for the plaques that eventually lead to Alzheimer’s.
Tanzi said, since 2010, his research has shown that:
So now the question has become, “If the amyloid has the ability to be anti-microbial, then what microbes in the brain are triggering the plaques?” Tanzi said.
In the new study, Tanzi said his team showed that the herpes viruses could “rapidly” induce amyloid plaque production in mice (within 24 to 48 hours); that the plaques are trapping the virus to protect the brain cells from viral infection; and that the mice bred with the ability to create amyloid beta were better able to fight brain infection than the mice without it. “So the amyloid is trying to do a good job of protecting the brain, but too much of it causes problems,” Tanzi said.
Tanzi concluded that it is “the seeding of amyloid” that causes plaque formation. “And herpes viruses and other microbes can rapidly seed amyloid beta,” he said.
He’s not the only one of late to point to viruses as precursors to dementia. He said researchers at by Mount Sinai Medical Center were first to find an overabundance of herpes viruses within the autopsied brains of Alzheimer’s sufferers. That team of researchers from the Icahn School of Medicine at Mount Sinai also published a paperrecently in Neuron supporting the role of viruses in Alzheimer’s disease. His and Mount Sinai’s labs have corroborated on the topic for some time, he said.
Tanzi cautions, however, that just because a person has one of the herpes viruses does not mean they will get Alzheimer’s. “We are not saying that herpes viruses cause Alzheimer’s. We are suggesting they are a risk factor that causes the formation of plaques that can then go on to become Alzheimer’s,” he said. “Just because you are positive for these viruses doesn’t mean you get Alzheimer’s disease. It just means we know it is activating the process that brings on Alzheimer’s more often. These viruses are the tip of the iceberg. Fungus, viruses, bacteria—there are dozens of microbes. A Taiwanese paper recently showed a large epidemiological segment of people on anti-viral drugs, specifically anti-herpes, that were protected against Alzheimer’s. The question will be which microbes beyond herpes play the biggest role in triggering the amyloid in the brain.”
In the meantime, the mapping of the brain’s microbiome continues. “At the end of the day, once we have a list of the most common microbes—whether they’re bacteria, viruses or yeast—then we will be thinking anti-microbial drugs,” Tanzi said. “Once we know what the most common microbes in the Alzheimer’s brain are triggering the amyloid production, we can start to develop treatments.”
He said those treatments will likely vary widely when it’s all said and done, including preventative antimicrobial drugs or vaccines that can stop germs from ever reaching the brain in the first place. “Drugs that stop plaques have to be used early but also drugs for inflammation, and also drugs that can hit the microbial infection that can trigger the plaques to begin with,” he said.
And it doesn’t end there. “There are other things that trigger plaques including genetics,” Tanzi said. “We have to find out what else. Infection acts as a seed. Other seeds might be air pollution which is just the right size to get in the nose and get through the blood brain barrier and mimic microbes.”
ut for now, Tanzi’s focus is microbes. And some would say his opinion is worth considering. Tanzi co-discovered three of the first Alzheimer’s disease genes and has identified several others in the Alzheimer’s Genome Project, which he directs. He also discovered the Wilson’s disease gene and participated in the discovery of several other neurological disease genes. Using a three-dimensional human stem cell-derived neural culture system he created, Tanzi is also developing therapeutics for Alzheimer’s including gamma secretase modulators and metal chaperones to lower beta-amyloid and tangle burden in the brain.
Named in 2015 as one of TIME100 Most Influential People in the World, Tanzi has published nearly 500 research papers and has received the highest awards in his field, including the Metropolitan Life Foundation Award and Potamkin Prize and the 2015 Smithsonian American Ingenuity Award. He co-authored the trade books “Decoding Darkness,” “Super Brain” and “Super Genes.”
Tanzi said he believes doctors will be managing Alzheimer’s disease—like they do heart disease and diabetes today—by 2025, if not sooner.
And he’s in good company. Scientists throughout the U.S. are going to great lengths to develop treatments for dementia. In an article featured in Elsevier’s Alzheimer’s & Dementia: Translational Research & Clinical Interventions, Jeffrey Cummings, of Cleveland Clinic’s Lou Ruvo Center for Brain Health reports that there were, as of January 2018, 112 agents in the Alzheimer’s disease treatment pipeline. Of these, Cummings reports, “63% are disease-modifying therapies, 22% are symptomatic cognitive enhancers, and 12% are symptomatic agents addressing neuropsychiatric and behavioral changes.” (Cummings review is based on clinical trial activity as recorded in clinicaltrials.gov, a comprehensive US government database. Federal law requires that all clinical trials conducted in the United States be registered on the site.) And the Alzheimer’s disease drug development pipeline is larger this year than it was in 2017.
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