Natural compound in basil may protect against Alzheimer's disease
pathology

Date:
October 5, 2021
Source:
University of South Florida (USF Health)
Summary:
Fenchol, a natural compound abundant in some plants including
basil, can help protect the brain against Alzheimer's disease
pathology, a preclinical study suggests. The team discovered a
sensing mechanism associated with the gut microbiome that explains
how fenchol reduces neurotoxicity in the Alzheimer's brain.



FULL STORY ========================================================================== 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 (@FrontiersIn), 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 (Ab) 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.

One of the two hallmark pathologies of Alzheimer's disease is hardened
deposits of Ab 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 Ab 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.

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 Ab
accumulation and death of neurons by stimulating FFAR2 signaling,
the microbiome sensing mechanism. When the researchers more closely
examined how fenchol modulates Ab-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, 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) Ab, 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 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.

========================================================================== Story Source: Materials provided by
University_of_South_Florida_(USF_Health). Original written by Anne
DeLotto Baier. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Atefeh Razazan, Prashantha Karunakar, Sidharth P. Mishra, Shailesh
Sharma, Brandi Miller, Shalini Jain and Hariom Yadav. Activation
of Microbiota Sensing - Free Fatty Acid Receptor 2 Signaling
Ameliorates Amyloid-b Induced Neurotoxicity by Modulating
Proteolysis-Senescence Axis. Frontiers in Aging Neuroscience,
2021 DOI: 10.3389/ fnagi.2021.735933 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211005101827.htm

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