International Journal of Molecular Sciences · Oct 16, 2026

EP2 and EP4 in Alzheimer's Disease: Cell-Dependent Signalling and Implications for Selective Targeting

By Zhao X, Zeng Y, Song Z et al.

Prostaglandin E2 (PGE₂) signalling influences amyloid-β (Aβ) processing, myeloid function, and neuronal injury in Alzheimer's disease (AD). Although EP2 and EP4 share Gs-cyclic adenosine monophosphate (cAMP) signalling, their cellular effects differ. This review integrates genetic, pharmacological, ageing, and AD-model evidence to assess receptor-selective targeting. EP2 deletion enhances myeloid Aβ handling and reduces microglia-mediated neuronal injury in experimental systems, providing a rationale for selective EP2 inhibition. In aged mice, PGE₂-EP2 signalling redirects glucose towards glycogen storage and restricts myeloid mitochondrial respiration; benefits from a predominantly peripheral antagonist suggest that some age-related outcomes may improve without high brain exposure. Chronic antagonist studies in AD models, however, show variable effects on inflammation, amyloid burden, and behaviour. EP4 exhibits contrasting cell-dependent actions: activation supports microglial Aβ uptake and inflammatory control, whereas signalling in some amyloid precursor protein (APP)-expressing cells promotes APP internalisation and Aβ production. Human AD evidence remains mainly tissue-based; EP2 antagonist testing has involved healthy volunteers, not patients with AD. These findings indicate that receptor selectivity alone is insufficient to predict therapeutic outcomes. Further studies should combine cell-specific receptor manipulation, measurements of central and peripheral exposure, and separate assessments of Aβ production, clearance, tissue injury, and functional outcomes.

doi.org/10.3390/ijms27209190 Open access PubMed 42941959 Interventions