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New theory on Alzheimer's disease prevention focuses on battling brain infection: Dr. Tanzi's work suggests that the buildup of toxic plaques in the brain may be a natural response to microbial invaders, and that it may be preventable.

For years, researchers looking for a cure for Alzheimer's disease (AD) focused on ridding the brain of accumulations of a toxic protein called beta-amyloid. The prevailing opinion was that the protein was a sort of brain trash whose accumulation was the precipitating factor in the AD process. Yet, even when scientists found ways to eliminate beta-amyloid from the brains of people with AD, the disease continued to progress.

Now, thanks to the work of Massachusetts General Hospital (MGH) neuroscientists and researchers Rudolph Tanzi, PhD, and Robert Moir, PhD, a new hypothesis has emerged that sees beta-amyloid as an integral part of the innate immune system, the purpose of which is to battle pathogens in the brain. According to this hypothesis, published last year in Science Translational Medicine, beta-amyloid becomes abnormally deposited in the brain when it detects and traps infectious agents that are activated within the brain or enter the brain through a leaky blood/brain barrier. The entrapment is accomplished by sticky plaques that, in turn, trigger the formation of another toxic protein--tau fibrils, or tangles--and lead to growing inflammation that causes increasing damage and brain cell death. A key memory region--the hippocampus--is at the center of this destructive process.



"Our research is still preliminary, but it suggests that rather than doing away with beta-amyloid, we might do better to concentrate on understanding and modifying the process by which low levels of bacteria, fungi, yeasts, and viruses enter the brain and trigger its build-up--and the good news is that we may be close to finding ways to do that," says Dr. Tanzi, who is Vice-Chair of Neurology and Director of MGH's Genetics and Aging Research Unit, and the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School.

In the following interview, we explore how Dr. Tanzi and his colleague's innovative approach to AD might help people protect themselves against AD and lead to new breakthroughs in treatment and prevention.

MMM: Can people translate your theories about the AD disease process into strategies that might help them avoid developing AD?

DR. TANZI: I believe so. We know that there are strategies people can use to help protect the brain against pathogens and discourage the immune-generated inflammatory processes, the spread of which leads to the destruction of brain cells and the downhill descent into dementia. Our work suggests that it may be possible to prevent the accumulation of beta-amyloid and the subsequent development of AD through measures that improve the ability of the immune system to protect the brain against invading infections and inflammation, especially in older age. I would advise people to:

1. Protect the blood-brain barrier:

The blood-brain barrier (BBB) is a web of tightly packed cells belonging to the tiny capillaries on the surface of the brain that separates the brain from the blood supply and prevents the entry of toxic substances and microbes. This important protective structure tends to weaken with age, as does the overall immune system. Strategies to strengthen this natural barrier include exercising, reducing stress, getting 7 to 8 hours of sleep at night, avoiding toxins, reducing dietary levels of sugar and cholesterol, and managing health conditions, such as high blood pressure, viral infections, and cerebrovascular disease.

2. Fight inflammation: Inflammation plays a major role in the neurodegenerative process. Strategies that help combat this aspect of the immune response include maintaining healthy teeth and gums; getting treatment for systemic infections; taking a daily low-dose antiinflammatory such as aspirin with your doctor's okay; and consuming an antiinflammatory diet with plenty of whole grains, vegetables (including celery and peppers), fruits, tree nuts, choline-rich eggs and beans, lean meat or fish (or no meat or fish in my case as a lacto-vegetarian), while avoiding junk food and processed foods such as refined carbohydrates, trans fats, and meats and dairy products with high levels of saturated fat.

3. Maintain healthy gut bacteria:

We're learning that, through the gut/brain connection, inflammation that starts in the gut often spreads through the body to the brain. Strategies to improve the intestinal biome can reduce this potentially negative effect on the brain. They include consuming prebiotics--non-digestible fiber compounds found in foods such as salad and roughage; raw or cooked onions or garlic; whole grains, and pulpy orange juice--that provide fuel for "good" bacteria; and consuming probiotics--foods containing active bacteria associated with lower levels of inflammation, such as active yogurt, kefir, sauerkraut, and pickles. Or one can consider a probiotic supplement with up to 50 billion live cultures.

4. Manage stress: We have recently reported that a meditation technique can lower the expression of genes involved in various aspects of Alzheimer's pathology. (Details of these recommendations can be found in my recent book, Super Genes, co-authored with Dr. Deepak Chopra.)

MMM: What led you to suspect that beta-amyloid was an immune agent?

DR. TANZI: After Dr. Moir noticed that beta-amyloid closely resembled antimicrobial peptides that the body uses to fight against pathogens in its separate immune system, we decided to determine whether beta-amyloid might function as an antimicrobial peptide in the brain. We observed that when we injected a pathogen into either mice or a mini-model of a human Alzheimer's brain with living cells in a Petri dish, the pathogen triggered the buildup of amyloid plaque within hours. The pathogen caused a seeding effect, in which the beta-amyloid attacked a microbe and surrounded it, producing fibrils that interacted with surrounding neurons. This interaction, in turn, caused the formation of tangles that led to inflammation and neuronal death in the model of human AD.

MMM: How might your theory translate into new approaches to AD prevention and treatment?

DR. TANZI: Our research suggests the importance of lifestyle changes that strengthen the blood/brain barrier and reduce inflammation as a way to help individuals avoid AD. It also implies that identifying and treating amyloid plaque buildup in the brain at the earliest possible time might help to halt the neurodegenerative process. Since our studies suggest that beta-amyloid may be protective, we should think about ways to dial amyloid down to a safe level instead of targeting the protein and eliminating it from the brain altogether. We are very close to having drugs that can do this.

Another approach might be to identify the type of microbe that is triggering beta-amyloid's antimicrobial function and attack these microbes with brain-permeable antibiotics. Vaccines or antibodies that target the infectious agent might also be developed. We are currently looking at AD brain tissue to identify pathogens trapped inside amyloid plaque to see which microbes seem to be more abundant. What we're finding suggests that viruses activated in the brain may be more likely to trigger the AD process than bacteria. In the future we intend to focus our efforts on these pathogens.
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Title Annotation:Rudolph Tanzi
Publication:Mind, Mood & Memory
Article Type:Interview
Geographic Code:1USA
Date:Aug 1, 2017
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