Major contributor to Alzheimer's disease discovered



The LSU Health New Orleans Neuroscience Center, the Departments of Cell Biology and Anatomy, Neurology, and Ophthalmology have collaborated on research led by Drs. Yuhai Zhao and Walter J. Lukiw that describes for the first time a pathway that starts in the gut and ends with a powerful pro-inflammatory toxin in brain cells that contributes to the onset of Alzheimer's disease (AD). They also describe a straightforward approach to stop it. Results are accessible here in Frontiers in Neurology.

The scientists discovered proof that a neurotoxic known as BF-LPS is produced in the human gastrointestinal (GI) tract by a molecule comprising an extremely potent microbially produced neurotoxin (lipopolysaccharide, or LPS), which is obtained from the Gram-negative bacteria Bacteroides fragilis.

According to Dr. Lukiw, LPSs are likely the most potent pro-inflammatory, neurotoxic glycolipids generated by microbes. Numerous labs, including our own, have found various LPS subtypes in the neurons of Alzheimer's disease-affected human brains.

In this study, the researchers describe how BF-LPS travels from the gut to the brain and how it works once it gets there. When BF-LPS escapes from the GI tract, it enters the blood brain barrier through the circulatory system. A protein that maintains cell integrity called neuron-specific neurofilament light (NF-L) is then inhibited and inflammation in brain cells increases. As shown in neurons affected by AD, a lack of this protein causes gradual neuronal cell shrinkage and ultimately cell death. Additionally, they claim that consuming enough dietary fiber can stop the process.

Three things distinguish this recently discovered pathogenic route as novel. The GI-tract microbiome is where the AD-stimulating pathway starts inside of us; as a result, it is quite "locally sourced" and active throughout our lives. A naturally occurring byproduct of GI-tract-based microbial metabolism is the very toxic neurotoxin BF-LPS. Dietary fiber intake can control the microbiome's abundance of Bacteroides fragilis, which is the source of the neurotoxic BF-LPS.

Or, to put it another way, "dietary-based approaches to balance the microbes 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 release of highly neurotoxic microbial-derived secretions, including BF-LPS and other forms of LPS," according to Lukiw.

The researchers come to the conclusion that new diagnostic and therapeutic approaches in the clinical management of Alzheimer's disease and other fatal, progressive, and age-related neurodegenerative disorders have a significant potential to result from a better understanding of the interaction between the GI tract-Central Nervous System axis and the GI-tract microbiome and Alzheimer's disease.

The average amount of fiber consumed daily by Americans is thought to be between 10 and 15 grams. Women under 50 should consume 25 grams daily, while males should consume 38 grams, according to the USDA. Women and men over 50 should each ingest 21 and 30 grams per day, respectively.

The sixth largest cause of mortality in the United States is Alzheimer's disease, which is the most frequently diagnosed dementia patient condition, according to the National Institutes of Health. According to experts, 5.8 million Americans aged 65 and older currently have Alzheimer's disease, and by 2050, there will be 13.8 million more cases nationwide.

Drs. Vivian Jaber and Nathan Sharfman from LSU Health New Orleans contributed as co-authors. Co-authoring with them was Aileen Pogue from Alchem Biotech Research in Toronto, Canada.

The Joe and Dorothy Dorsett Innovation in Science Health Aging Award, the Brown Foundation, the National Institutes on Aging of the National Institutes of Health, and LSU Health New Orleans all provided funding for the study.

Louisiana State University Health Sciences Center

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