Natural compound in basil may protect against Alzheimer’s disease, study says

Fenchol, a natural compound abundant in some plants including basil, could help protect the brain against Alzheimer’s disease pathology, according to a preclinical study led by University of South Florida Health (USF Health) published in the journal Frontiers in Aging Neuroscience.

In the study, researchers discovered a sensing mechanism associated with the gut microbiome that explains how fenchol reduces neurotoxicity in the Alzheimer’s brain. Emerging evidence indicates that short-chain fatty acids (SCFAs)– metabolites produced by beneficial gut bacteria and the primary source of nutrition for cells in the colon -- contribute to brain health. The abundance of SCFAs is often reduced in older patients with mild cognitive impairment and Alzheimer’s disease, the most common form of dementia. However, how this decline in SCFAs contributes to Alzheimer’s disease progression remains largely unknown.

Gut-derived SCFAs that travel through the blood to the brain can bind to and activate free fatty acid receptor 2 (FFAR2), a cell signaling molecule expressed on brain cells called neurons.

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

The researchers delved into molecular mechanisms to explain how interactions between the gut microbiome and the brain might influence brain health and age-related cognitive decline. They set out to uncover the “previously unknown” function of FFAR2 in the brain.

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

Then, they performed large-scale virtual screening of more than 144,000 natural compounds to find potential candidates that could mimic the same beneficial effect of microbiota produced SCFAs in activating FFAR2 signaling. Identifying a natural compound 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 researchers said.

The research team narrowed 15 leading compound candidates to the most potent one. Fenchol, a plant-derived compound that gives basil its aromatic scent, was best at binding to the FFAR’s active site to stimulate its signaling.

Further experiments in human neuronal cell cultures, as well as Caenorhabditis (C.) elegans (worm) and mouse models of Alzheimer’s disease demonstrated that fenchol significantly reduced excess Aβ accumulation and death of neurons by stimulating FFAR2 signaling, the microbiome sensing mechanism. When the researchers more closely examined 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 Alzheimer’s disease pathology.

Zombie cells stop replicating and die a slow death. Meanwhile, they build up in diseased and aging organs, create a damaging inflammatory environment, and send stress or death signals to neighboring healthy cells, which eventually also change into harmful zombie cells or die, the researchers said.

More research is needed, including clinical studies in humans, the researchers said. In exploring fenchol as a possible approach for treating or preventing Alzheimer’s pathology, the researchers will look to answer several questions, including whether fenchol consumed in basil itself would be more or less bioactive than isolating and administering the compound in a pill.