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

Atefeh Razazan,Sidharth P Mishra,Shailesh Sharma,Shalini Jain,Prashantha Karunakar,Hariom Yadav,Brandi Miller

doi:10.3389/fnagi.2021.735933

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.

Highlights

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in older adults(Jonsson et al, 2013)
We demonstrated that suppressing free fatty acid receptor 2 (FFAR2; a G-protein-coupled receptor activated by short chain fatty acids (SCFAs)) contributes to Aβ accumulation and discovered that Fenchol, a natural compound, decreased AD pathology by activating FFAR2 signaling
The inhibition of FFAR2 using a small compound inhibitor (CATPB) further exacerbated Aβ-induced cell death in these cells (Figures 1C,D). These results indicate that FFAR2 is expressed in the neuronal cells and its inhibition exacerbates the detrimental effects of increased Aβ and decreases the survival of neuronal cells, suggesting that the activation of FFAR2 signaling may reduce Aβinduced neuronal toxicity

Summary

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in older adults(Jonsson et al, 2013). Current therapies that are targeted to reduce Aβ levels are not successful, but there is a plethora of literature suggesting that an increased Aβ accumulation is causal for neurodegeneration in AD pathology. Reducing their accumulation can be an effective strategy to prevent AD progression. Inflammatory cytokines instigate Aβ production by activating specific transcription factors, such as interferon-induced transmembrane protein three in neurons and astrocytes (Hur et al, 2020) Together, these abnormalities further deteriorate brain health and functions, such as memory and learning behaviors (He et al, 2013). Because we do not fully understand the pathology of Aβ production and its accumulation and clearance, strategies to reduce the accumulation of Aβ in the neuronal cells and, ameliorate neurodegeneration and AD pathology, are lacking

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Conclusion