# Allosteric activation of a cell-type-specific GPR120 inhibits amyloid pathology of Alzheimer’s disease

## TL;DR

Unsaturated fatty acids in black rice activate a brain receptor to reduce Alzheimer's amyloid plaques and improve cognition in mice.

## Contribution

Discovery of cell-type-specific GPR120 activation by ALA and EDA as a novel therapeutic mechanism for Alzheimer’s disease.

## Key findings

- ALA and EDA inhibit amyloid pathology and rescue cognition in Alzheimer’s disease mouse models.
- GPR120 activation by ALA and EDA promotes phagocytosis and clearance of β-amyloid aggregates.
- Cell-type-specific deletion of GPR120 or Gαi1 abolishes the therapeutic effects of ALA and EDA.

## Abstract

Black rice diets are enriched with unsaturated fatty acids that are thought to be beneficial for neurodegenerative disorders in aging. Here we find that α-linolenic acid (ALA) and 11,14-eicosadienoic acid (EDA), which are naturally enriched in black rice, inhibit amyloid pathology, rescue cognition and extend lifespan in mouse preclinical models of Alzheimer’s disease via allosteric activation of G protein-coupled receptor 120 (GPR120) in plaque-associated macrophages and activated microglia. We generate the structures of GPR120 bound to ALA and EDA. We demonstrate that ALA and EDA allosterically modulate and synergistically activate GPR120 for macrophagic phagocytosis and clearance of β-amyloid aggregates in Alzheimer’s disease mice. A cell-type-specific deletion of GPR120, or Gαi1, completely abrogates the therapeutic effects of ALA and EDA. This deletion can be rescued by a constitutive active Gαi1–Q204L. These findings show a cell-type-specific function of GPR120 in the brain and provide an enriched allosteric mechanism of GPR120 activation for the treatment of Alzheimer’s disease.

He, Wang, Shen, Dong and colleagues find that unsaturated fatty acids enriched in a black rice diet inhibit amyloid pathology, rescue cognition and restore physiological lifespan in mouse models of Alzheimer’s disease via allosteric activation of GPR120.