Exploring GPR120/FFAR4 pharmacology: Unveiling novel therapeutic avenues through molecular signaling pathways for Alzheimer's disease intervention

Abstract

G-protein-coupled receptors (GPCRs) are a major class of membrane proteins involved in numerous physiological and pathological processes. Among them, free fatty acid receptor 4 (FFAR4/GPR120), activated by long-chain free fatty acids, has shown anti-inflammatory effects and is expressed in the brain-implicating its role in neurodegenerative diseases like Alzheimer's disease (AD). AD is characterized by brain atrophy, cognitive decline, and neuroinflammation, involving complex signaling networks. This review explores the pharmacological relevance of GPR120/FFAR4 in AD, focusing on its involvement in neuroinflammatory, amyloidogenic, and intracellular signaling cascades. Targeting GPR120 may help modulate chronic inflammation and amyloid-β accumulation. Additionally, activation of nuclear receptors and regulation of pathways such as MAPK, NLRP3, PPARs, and cAMP have shown promise in mitigating AD pathology. Despite the complexity of brain signaling, GPR120 emerges as a compelling multitarget therapeutic receptor. These insights provide a foundation for developing novel anti-inflammatory strategies in AD treatment.

Keywords: GPCR; MAPK; NLRP3; Neuroinflammation; Neuroprotection; PPARs; Therapeutic targets.

Fig. 1

Molecular ligands of GPR120.

Fig. 2

GPR120 distribution and physiological functions.

Fig. 3

GPR120 pharmacological role.

Fig. 4

NLRP3 signaling pathway: Activation of the NLRP3 inflammasome signaling pathway stimulates the production of several inflammasome components such as protein NLRP3, pro-IL-1β, and pro-IL-18. NLRP3 inflammasome oligomerization leads to caspase-1 activation and IL-1β and IL-18 release, subsequently resulting in neurodegenerative disease.

Fig. 5

Proteolytic breakdown of amyloid precursor protein (APP) and Aβ biogenesis.

Fig. 6

Amyloidogenic and non-amyloidogenic processing pathway of APP.

Fig. 7

Structures of omega-3 fatty acids.

Fig. 8

The ERK- mediate signaling pathway.

Fig. 9

cAMP signaling pathway and cAMP in vascular theory A) ACs promote intracellular cAMP accumulation, which activates protein kinase A (PKA), leading to phosphorylation of cAMP-response element binding protein (CREB), which translocates to the nucleus anti-inflammatory cytokines and production of pro-resolving mediators. B) cAMP exerts a protective effect on the integrity of the endothelium in the BBB, and any inflammatory mediators result in the development of neurodegenerative diseases.

Fig. 10

Schematic of fatty acids receptor system.

Fig. 11

Crystal structure (PDB-ID: 3DZY) of the PPARs.