| First Author | Razazan A | Year | 2021 |
| Journal | Front Aging Neurosci | Volume | 13 |
| Pages | 735933 | PubMed ID | 34707491 |
| Mgi Jnum | J:349686 | Mgi Id | MGI:6784953 |
| Doi | 10.3389/fnagi.2021.735933 | Citation | Razazan A, et al. (2021) Activation of Microbiota Sensing - Free Fatty Acid Receptor 2 Signaling Ameliorates Amyloid-beta Induced Neurotoxicity by Modulating Proteolysis-Senescence Axis. Front Aging Neurosci 13:735933 |
| abstractText | Multiple emerging evidence indicates that the gut microbiota contributes to the pathology of Alzheimer's disease (AD)-a debilitating public health problem in older adults. However, strategies to beneficially modulate gut microbiota and its sensing signaling pathways remain largely unknown. Here, we screened, validated, and established the agonists of free fatty acid receptor 2 (FFAR2) signaling, which senses beneficial signals from short chain fatty acids (SCFAs) produced by microbiota. The abundance of SCFAs, is often low in the gut of older adults with AD. We demonstrated that inhibition of FFAR2 signaling increases amyloid-beta (Abeta) stimulated neuronal toxicity. Thus, we screened FFAR2 agonists using an in-silico library of more than 144,000 natural compounds and selected 15 of them based on binding with FFAR2-agonist active sites. Fenchol (a natural compound commonly present in basil) was recognized as a potential FFAR2 stimulator in neuronal cells and demonstrated protective effects against Abeta-stimulated neurodegeneration in an FFAR2-dependent manner. In addition, Fenchol reduced AD-like phenotypes, such as Abeta-accumulation, and impaired chemotaxis behavior in Caenorhabditis (C.) elegans and mice models, by increasing Abeta-clearance via the promotion of proteolysis and reduced senescence in neuronal cells. These results suggest that the inhibition of FFAR2 signaling promotes Abeta-induced neurodegeneration, while the activation of FFAR2 by Fenchol ameliorates these abnormalities by promoting proteolytic Abeta-clearance and reducing cellular senescence. Thus, stimulation of FFAR2 signaling by Fenchol as a natural compound can be a therapeutic approach to ameliorate AD pathology. |
