Discovering a major contributor to Alzheimer’s disease

Discovering a major contributor to Alzheimer's disease

Research led by Drs. Yuhai Zhao and Walter J Lukiw at the LSU Health New Orleans Neuroscience Center and the Departments of Cell Biology and Anatomy, Neurology and Ophthalmology, reports for the first time a pathway that begins in the gut and ends with a potent pro-inflammatory toxin in brain cells contributing to the development of Alzheimer’s disease (AD). They also report a simple way to prevent it. Results are published in Frontiers in Neurology.

The researchers found evidence that a molecule containing a very potent microbial-generated neurotoxin (lipopolysaccharide or LPS) derived from the Gram-negative bacteria Bacteroides fragilis in the human gastrointestinal (GI) tract generates a neurotoxin known as BF-LPS.

“LPSs in general are probably the most potent microbial-derived pro-inflammatory neurotoxic glycolipids known,” says Dr. Lukiw. “Many laboratories, including our own, have detected different forms of LPS within neurons of the Alzheimer’s disease-affected human brain.”

In this study, the researchers detail the pathway of BF-LPS from the gut to the brain and its mechanisms of action once there. BF-LPS leaks out of the GI tract, crosses the blood brain barrier via the circulatory system, and accesses brain compartments. Then it increases inflammation in brain cells and inhibits neuron-specific neurofilament light (NF-L,) a protein that supports cell integrity. A deficit of this protein leads to progressive neuronal cell atrophy, and ultimately cell death, as is observed in AD-affected neurons. They also report that adequate intake of dietary fiber can head off the process.

The novel features of this newly described pathological pathway are threefold. The AD-stimulating pathway begins inside of us—in our GI-tract microbiome—and therefore is very “locally sourced” and active throughout our lives. The highly potent neurotoxin BF-LPS is a natural by-product of GI-tract-based microbial metabolism. Bacteroides fragilis abundance in the microbiome, which is the source of the neurotoxin BF-LPS, can be regulated by dietary fiber intake.

“Put another way, dietary-based approaches to balance the microorganisms in the microbiome may be an attractive means to modify the abundance, speciation, and complexity of enterotoxigenic forms of AD-relevant microbes and their potential for the pathological discharge of highly neurotoxic microbial-derived secretions that include BF-LPS and other forms of LPS,” Lukiw explains.

The researchers conclude that an improved understanding of the interaction between the GI tract-Central Nervous System axis and the GI-tract microbiome and Alzheimer’s disease has considerable potential to lead to new diagnostic and therapeutic strategies in the clinical management of Alzheimer’s disease and other lethal, progressive, and age-related neurodegenerative disorders.

It has been estimated that Americans eat 10–15 grams of fiber a day on average. The USDA recommends that women up to age 50 consume 25 grams a day and men 38 grams. Over age 50, women and men should consume 21 and 30 grams daily, respectively.

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