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

  • Nat Aging. 2025 Dec 19. doi: 10.1038/s43587-025-01028-4.
Aodi He  #  1  2 ,  Yue Wang  #  1  3 ,  Yuhang Shen  #  1  2  3 ,  Zhiqiang Dong  #  4 ,  Lingli Luo  1  3 ,  Xiangyu Ge  1  3 ,  Xinlu Liu  1  3 ,  Yue Mao  1  3 ,  Tongmei Zhang  1  5 ,  Xinyan Li  1  2 ,  Hao Li  1  3 ,  Wei Jing  1  2  6 ,  Ling-Qiang Zhu  1  3 ,  Qifa Zhang  7 ,  Youming Lu  8  9  10
Affiliations
  • 1. Innovation Center for Brain Medical Sciences of the Ministry of Education, Huazhong University of Science and Technology, Wuhan, China.
  • 2. Department of Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3. Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4. College of Biomedicine and Health, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China.
  • 5. Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 6. Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 7. National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, China. [email protected].
  • 8. Innovation Center for Brain Medical Sciences of the Ministry of Education, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 9. Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 10. Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • # Contributed equally.
PMID: 41419665 DOI: 10.1038/s43587-025-01028-4
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.

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