Activation of Microbiota Sensing – Free Fatty Acid Receptor 2 Signaling Ameliorates Amyloid-β Induced Neurotoxicity by Modulating Proteolysis-Senescence Axis

Abstract

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 (Aβ) 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 Aβ-stimulated neurodegeneration in an FFAR2-dependent manner. In addition, Fenchol reduced AD-like phenotypes, such as Aβ-accumulation, and impaired chemotaxis behavior in Caenorhabditis (C.) elegans and mice models, by increasing Aβ-clearance via the promotion of proteolysis and reduced senescence in neuronal cells. These results suggest that the inhibition of FFAR2 signaling promotes Aβ-induced neurodegeneration, while the activation of FFAR2 by Fenchol ameliorates these abnormalities by promoting proteolytic Aβ-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.

Neuroprotective effect of short‐chain fatty acids against oxidative stress‐induced SH‐SY5Y injury via GPR43‐dependent pathway

“…SCFAs represent an emerging target for the aging brain and age‐related neurodegenerative diseases in recent years. Although it has been shown that SCFAs can directly activate specific G protein‐coupled receptors (GPCRs), including GPR43, GPR41, and GPR109a (Dalile et al, 2019), the expression of these GPCRs is detected in several cell types in the central nervous system, including neurons and glia (Erny et al, 2015; Razazan et al, 2021; Tran & Mohajeri, 2021). However, the exact mechanism by which SCFAs is involved in age‐related neurodegenerative diseases is still unclear.…”

“…GraphPad Prism 7.0 was used to accomplish the statistical analysis. A sample size was estimated based on previous neuroblastoma cell line for neurodegenerative studies (Razazan et al, 2021; Wu et al, 2022) to obtain biometrical sample size estimation and the assumptions of a power of 0.8 and a type I error rate of 0.05. Data was expressed as median ± interquartile range.…”

“…Specifically, the serum level of SCFAs is significantly lower in Parkinson's disease patients compared to healthy controls (Unger et al, 2016; van Kessel & El Aidy, 2019). In addition, Razazan et al show that a suppression of the GPR43 receptor causes an increase in Aβ‐induced neurotoxicity in SH‐SY5Y cells, while an activation of the GPR43 receptor ameliorates amyloid‐beta (Aβ)‐induced neurotoxicity (Razazan et al, 2021). Altogether, the accumulation of data suggests the beneficial effect of SCFAs on neurodegeneration.…”

Epigenetic Alterations of Brain Non-Neuronal Cells in Major Mental Diseases

“…It is also known that the gut microbial population (the microbiome or microbiota) collectively contains 100 times more genes than humans and makes numerous compounds, nutrients, and vitamins that are required for the epigenetic fine tuning of brain genes’ functions, as reviewed elsewhere [ 34 ]. As an example, the gut microbiota produces short-chain fatty acids (SCFAs), which are well-known epigenetic modifiers and protect neurons via free fatty acid receptor 2 (FFAR2) signaling [ 141 ].…”

Short Chain Fatty Acids Protect the Cognitive Function of Sepsis Associated Encephalopathy Mice via GPR43

“…Acetate, one of the SCFAs, could suppress neuroinflammation and attenuate perioperative neurocognitive disorders by binding to GPR43 according to a recent research (14). The activation of GPR43 also ameliorates the accumulation of amyloid-β and neuroinflammation in Alzheimer disease (16). However, whether GPR43 exerts an anti-neuroinflammation effect by interacting with SCFAs in SAE or not is still unclear.…”