Natural Basil Compound May Protect Against Alzheimer’s Disease

The team led by the University of South Florida Health finds that the compound fenchol has the same beneficial effect as the gut-derived metabolites in reducing the neurotoxic beta-amyloid in the brain.

Fenchol, a natural compound abundant in certain plants including basil, may help protect the brain against Alzheimer’s pathology of the disease, suggests a preclinical study conducted by researchers at the University of South Florida (USF Health).

The new study published on October 5, 2021 in the The frontiers of the neurosciences of aging, discovered a sensing mechanism associated with the gut microbiome that explains how fenchol reduces neurotoxicity in Alzheimer’s brain.

New evidence indicates that short chain fatty acids (SCFAs) – metabolites produced by beneficial gut bacteria and the primary source of nutrition for cells in your colon – contribute to brain health. The abundance of SCFAs is often reduced in elderly patients with mild cognitive impairment and Alzheimer’s disease, the most common form of dementia. However, how this drop in SCFA contributes to the progression of Alzheimer’s disease remains largely unknown.

SCFAs of intestinal origin that travel through the blood to the brain can bind to free fats and activate them. acid receptor 2 (FFAR2), a cell signaling molecule expressed on brain cells called neurons.

“Our study is the first to discover that stimulation of the FFAR2 detection mechanism by these microbial metabolites (SCFA) may be beneficial in protecting brain cells against the toxic accumulation of beta-amyloid (Aβ) protein associated with disease. ‘Alzheimer’s,’ said lead researcher Hariom Yadav, PhD, professor of neurosurgery and brain repair at USF Health Morsani College of Medicine, where he directs the USF Center for Microbiome Research.

One of the two pathologies characteristic of Alzheimer’s disease are the hardened deposits of Aβ which clump together between nerve cells to form plaques of amyloid proteins in the brain. The other is the neurofibrillary entanglement of the tau protein inside brain cells. These conditions contribute to the loss and death of neurons that ultimately lead to the onset of Alzheimer’s disease, a neurodegenerative disease characterized by loss of memory, thinking skills and other cognitive abilities.

Dr Yadav and colleagues are exploring molecular mechanisms to explain how interactions between the gut microbiome and the brain might influence brain health and age-related cognitive decline. In this study, said Dr Yadav, the research team set out to uncover the “previously unknown” function of FFAR2 in the brain.

The researchers first showed that the inhibition of the FFAR2 receptor (thus blocking its ability to “detect” SCFAs in the environment outside the neuronal cell and to transmit the signaling inside the cell) contributes to the abnormal accumulation of the protein Aβ causing neurotoxicity linked to Alzheimer’s disease.

Next, they performed a large-scale virtual screening of over 144,000 naturally occurring compounds to find potential candidates that could mimic the same beneficial effect of microbiota-produced SCFAs in activating FFAR2 signaling. It is important to identify a natural compound alternative to SCFAs to optimally target the FFAR2 receptor on neurons, as cells in the gut and other organs consume most of these microbial metabolites before they reach the brain through the bloodstream, Dr. Yadav noted.

Dr. Yadav’s team narrowed down the top 15 candidate compounds to the most potent. Fenchol, a plant-derived compound that gives basil its aromatic scent, was best for binding to the active site of FFAR to stimulate its signaling.

Further experiments on human neuronal cell cultures, as well as Caenorhabditis (C.) elegans (worm) and mouse models of Alzheimer’s disease have shown that fenchol significantly reduced excessive Aβ accumulation and neuronal death by stimulating FFAR2 signaling, the microbiome’s detection mechanism. When researchers took a closer look at how fenchol modulates Aβ-induced neurotoxicity, they found that the compound decreased senescent neuronal cells, also known as “zombie” cells, commonly found in brains with the disease. Alzheimer’s.

Zombie cells stop replicating and die slowly. Meanwhile, Dr Yadav said, they accumulate in diseased and aging organs, create a damaging inflammatory environment, and send signals of stress or death to neighboring healthy cells, which also eventually turn into harmful zombie cells. or die.

“Fenchol actually affects the two related mechanisms of senescence and proteolysis,” Dr Yadav said of the intriguing findings from the preclinical study. “It reduces the formation of half-dead zombie neuronal cells and also increases the breakdown of (non-functional) Aβ, so that amyloid protein is cleared from the brain much faster.”

Before you start tossing a lot of extra basil into your spaghetti sauce or whatever else you eat to help prevent dementia, more research is needed, including in humans.

By exploring fenchol as a possible approach to treat or prevent Alzheimer’s disease, the USF Health team will seek answers to several questions. A key point is whether the fenchol consumed in the basil itself would be more or less bioactive (effective) than isolating and administering the compound in a pill, Dr Yadav said. “We also want to know if a potent dose of basil or fenchol, if it could be given as a nasal spray, would be a faster way to get the compound into the brain.”

Reference: “Activation of microbiota detection – Free fatty acid receptor 2 signaling improves neurotoxicity induced by amyloid-β by modulating the proteolysis-senescence axis” by Atefeh Razazan, Prashantha Karunakar, Sidharth P. Mishra , Shailesh Sharma, Brandi Miller, Shalini Jain and Hariom Yadav, October 5, 2021, The frontiers of the neurosciences of aging.
DOI: 10.3389 / fnagi.2021.735933

USF Health-led research was funded in part by grants from the National Institutes of Health, the US Department of Defense, and the NIH-funded Wake Forest Clinical and Translational Science Institute.