A USF Health-led team finds that the compound fenchol has the same beneficial effect as gut-derived metabolites in reducing neurotoxic amyloid-beta in the brain

TAMPA, Fla. (Oct. 5, 2021) – Fenchol, a natural compound abundant in some plants including basil, can help protect the brain against Alzheimer’s disease pathology, a preclinical study led by University of South Florida Health (USF Health) researchers suggests.

The new study published Oct. 5 in the Frontiers in Aging Neuroscience, 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 your 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.

“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 toxic accumulation of the amyloid-beta (Aβ) 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.

Study principal investigator Hariom Yadav, PhD, directs the USF Microbiome Research Center housed at the USF Health Morsani College of Medicine. | Photo by Allison Long, USF Health Communications and Marketing

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.

Dr. Yadav and his collaborators delve into 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, Dr. Yadav said, the research team 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, Dr. Yadav noted.

Dr. Yadav’s 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.

Alzheimer’s disease model of the worm C. elegans treated with the plant-derived compound fenchol (Above) and with a DMSO placebo (Below). Fenchol reduced accumulation of amyloid-β (green dots) in the organism’s head, compared to the placebo. | Images courtesy of Hariom Yadav, PhD, of the University of South Florida, first appeared as Fig. 4d in Frontiers in Aging Neuroscience, DIO: 10.3389/fnagi.2021.735933

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.

Zombie cells stop replicating and die a slow death. Meanwhile, Dr. Yadav said, 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.

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

Before you start throwing lots of extra basil in your spaghetti sauce or anything else you eat to help stave off dementia, more research is needed — including in humans.

In exploring fenchol as a possible approach for treating or preventing Alzheimer’s pathology, the USF Health team will seek answers to several questions. A key one is whether fenchol consumed in 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 whether a potent dose of either basil or fenchol delivered by nasal spray would be a quicker way to get the compound into the brain.”

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

About USF Health
USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the Taneja College of Pharmacy, the School of Physical Therapy and Rehabilitation Sciences, the Biomedical Sciences Graduate and Postdoctoral Programs, and USF Health’s multispecialty physicians group. The University of South Florida is a high-impact global research university dedicated to student success. Over the past 10 years, no other public university in the country has risen faster in U.S. News and World Report’s national university rankings than USF. For more information, visit health.usf.edu

About Frontiers
Frontiers is one of the largest and highest-cited open access publishers in the world. Access to research results and data is open, free and customized online to help solve the critical challenges we face as humanity. All journals are led and peer-reviewed by editorial boards of more than 100,000 top researchers across more than 900 academic disciplines. https://twitter.com/FrontNeurosci

Tampa, Fla. (April 10,  2012) – A research team led by the University of South Florida’s Department of Psychiatry & Behavioral Neurosciences has found that a fragment of the amyloid precursor protein (APP) — known as sAPP-α and associated with Alzheimer’s disease — appears to regulate its own production.  The finding may lead to ways to prevent or treat Alzheimer’s disease by controlling the regulation of APP.

Their preclinical study is published online today in Nature Communications.

“The purpose of this study was to help better understand why, in most cases of Alzheimer’s disease, the processing of APP becomes deregulated, which leads to the formation of protein deposits and neuron loss,” said study senior author Dr. Jun Tan, professor of psychiatry and the Robert A. Silver Chair, Rashid Laboratory for Developmental Neurobiology at the USF Silver Child Development Center.   “The many risk factors for Alzheimer’s disease can change the way APP is processed, and these changes appear to promote plaque formation and neuron loss.”

Microscopic image showing the merging of the amyloid precursor protein fragment,
sAPP-α, and the APP-converting enzyme BACE 1, in neuronal cells.  This co-localization
suggests that sAPP-α may serve as the body’s mechanism to inhibit BACE1  activity and
thus lower production of the toxic amyloid beta characteristic of Alzheimer’s disease.

An estimated 30 million people worldwide and 5 million in the U.S. have Alzheimer’s.  With the aging of the “Baby Boom” generation, the prevalence of the debilitating disease is expected to increase dramatically in the U.S. in the coming years.  Currently, there are no disease-modifying treatments to prevent, reverse or halt the progression of Alzheimer’s disease, only medications that may improve symptoms for a short time.

“For the first time, we have direct evidence that a secreted portion of APP itself, so called ‘ sAPP-α,’ acts as an essential stop-gap mechanism,” said the study’s lead author Dr. Demian Obregon, a resident specializing in research in the Department of Psychiatry & Behavioral Neurosciences at USF Health. “Risk factors associated with Alzheimer’s disease lead to a decline in sAPP-α levels, which results in excessive activity of a key enzyme in Aβ formation.”

Dr. Demian Obregon is one of the study's coauthors.

In initial studies using cells, and in follow-up studies using mice genetically engineered to mimic Alzheimer’s disease, the investigators found that the neutralization of sAPP-α leads to enhanced Aβ formation.  This activity depended on  sAPP-α’s ability to associate with the APP-converting enzyme, BACE1.  When this interaction was blocked,  Aβ formation was restored.

The authors suggest that through monitoring and correcting low sAPP-α levels, or through enhancing its association with BACE, Alzheimer’s disease may be prevented or treated.

Dr. Demian Obregon and Dr. Lucy Hou of the USF Department of Psychiatry and Behavioral Neurosciences, the study’s lead authors, collaborated with colleagues from the Laboratory of Neurosciences at the National Institute on Aging and colleagues at the USF Center for Aging and Brain Repair, the James A. Haley Veterans’ Hospital and Saitama Medical University in Japan.  Other study authors included: Juan Deng, MD, Brian Giunta, MD, Jun Tian, BS, Donna Darlington, MS, Md Shahaduzzaman, MD, Yuyuan Zhu, MD, PhD, Takashi Mori, DVM, PhD, and Mark P. Mattson, PhD.

The research was supported by a grant from the National Institutes of Health, National Institute on Aging, and a Veterans Affairs Merit grant.

– USF Health –

USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician’s Group. The University of South Florida is a global research university ranked 34th in federal research expenditures for public universities.

Media contact:
Anne DeLotto Baier, USF Health Communications, abaier@health.usf.edu or (813) 974-3300