Scientists at the University of South Florida Health (USF Health) have discovered a new mechanism that helps neurons sense signals from the gut microbiome. The finding explains how fenchol—a natural compound found in basil and other plants—reduces Alzheimer’s disease-associated neurotoxicity in cell culture and in animal models.

The preclinical study was reported in the article, “Activation of Microbiota Sensing-Free Fatty Acid Receptor 2 Signaling Ameliorates Amyloid-β Induced Neurotoxicity by Modulating Proteolysis-Senescence Axis,” published in the journal Frontiers in Aging Neuroscience.

Beneficial bacteria in our gut are known to produce short-chain fatty acids (SCFAs) as a byproduct of their metabolisms. These not only provide nutrients to cells in the colon but also contribute to brain health. Patients with mild cognitive impairment (MCI), dementia, and Alzheimer’s disease often have reduced levels of SCFAs. However, exactly how reduced levels of SCFAs contribute to Alzheimer’s disease has been unclear.

This new study provides evidence that gut-derived SCFAs can bind and activate free fatty acid receptor 2 (FFAR2) on neurons in the brain, decreasing amyloid beta-induced neurotoxicity.

Hariom Yadav, PhD, professor of neurosurgery and brain repair at USF Health, studies how the gut microbiome affects brain health and age-related cognitive decline.

“Our study is the first to discover that stimulation of the FFAR2 sensing mechanism by these microbial metabolites (SCFAs) can be beneficial in protecting brain cells against the toxic accumulation of the amyloid-beta protein associated with Alzheimer’s disease,” said principal investigator Hariom Yadav, PhD, professor of neurosurgery and brain repair at the USF Health Morsani College of Medicine, where he directs the USF Center for Microbiome Research. Yadav’s team focuses on how the gut microbiome affects brain health and age-related cognitive decline.

Alzheimer’s disease is a devastating neurodegenerative disease where patients progressively lose their memory and other cognitive skills. Long before cognitive decline starts to manifest, amyloid beta protein plaques and tangles of tau protein begin to deposit in the brain, causing neuroinflammation and neuronal death.

In this study, the researchers blocked the ability of FFAR2 receptors to sense SCFAs and demonstrated that this contributes to the abnormal buildup of the amyloid beta protein causing neurotoxicity linked to Alzheimer’s disease.

Since SCFA levels are reduced in Alzheimer’s disease patients, the researchers next tried to identify other natural compounds that mimic SCFAs and activate FFAR2 signaling. Toward this end, they conducted a large-scale in silico screen of more than 144,000 natural compounds.

Yadav noted that identifying a natural alternative to SCFAs to optimally target the FFAR2 receptor on neurons is important, because cells in the gut and other organs consume most of these microbial metabolites before they reach the brain through blood circulation.

The team narrowed 15 leading candidates to the most potent one: fenchol. This aromatic compound binds to FFAR2’s active site and stimulates neuronal signaling.

Through experiments in human neuronal cell cultures, Caenorhabditis elegans, and mouse models of Alzheimer’s disease, the researchers showed that fenchol triggers FFAR2 signaling, reducing excess amyloid beta accumulation and neuronal death. For instance, the authors showed fenchol increases the lifespan of C. elegans that overexpress human amyloid beta proteins.

To better understand the cellular mechanisms affected by fenchol that allow it to modulate neurotoxicity, the researchers explored cellular lytic mechanisms and aging. They showed fenchol treatment increases the activity of hydrolytic cellular compartments called lysosomes.

This, the authors say, suggests fenchol increases a process called autophagy in neuronal cells. Literally meaning “self-eating,” autophagy is a lysosome-dependent mechanism whereby a cell removes its unnecessary or nonfunctional components, allowing recycling of the building blocks of biomolecules.

Whereas neurons treated with amyloid beta show increased aging, the researchers show fenchol treatment decreases aging neuronal cells. According to Yadav, senescent cells build up in diseased and aging organs, and send inflammatory stress or death signals to neighboring healthy cells, which eventually also age or die.

In addition, the researchers showed fenchol treatment does not change protein ubiquitinylation—a form of post-translational modification that can mark a protein for destruction. However, fenchol increases proteasomal activity—the machinery that degrades proteins—in human neuroblastoma-derived cells, in C. elegans, and in the cerebral cortex and hippocampus of an Alzheimer’s disease mouse model. This, the authors claimed, indicates fenchol reduces and clears amyloid beta accumulation by increasing proteasomal activity in the neuronal cells, thus reducing neurotoxicity.

“Fenchol affects the two related mechanisms of senescence and proteolysis,” said Yadav. “It reduces the formation of half-dead zombie neuronal cells and also increases the degradation of (nonfunctioning) amyloid beta, so that it is cleared from the brain much faster.”

In future studies, the USF Health team will explore the possibility of using fenchol to treat or prevent Alzheimer’s pathology. They will investigate the comparative efficacy of fenchol consumed directly through basil or isolated and administered as a pill.

Yadav added, “We also want to know whether a potent dose of either basil or fenchol would be a quicker way to get the compound into the brain.”

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