EP2 and EP4 in Alzheimer’s Disease: Cell-Dependent Signalling and Implications for Selective Targeting
- 1School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, No. 300 Xueshi Road, Yuelu District, Changsha 410208, China
- 2Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha 410208, China
- 3Medical School, Hunan University of Chinese Medicine, No. 300 Xueshi Road, Yuelu District, Changsha 410208, China
Abstract
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.
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BibTeX
@article{zhao2026alzheimers,
title = {{EP2 and EP4 in Alzheimer’s Disease: Cell-Dependent Signalling and Implications for Selective Targeting}},
author = {Xi Zhao and Youjia Zeng and Zhenyan Song and Jiawei He and Qijun He and Han Lin and Lu Liu and Wenjing Yu and Shaowu Cheng},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209190},
url = {https://www.mdpi.com/1422-0067/27/20/9190},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - EP2 and EP4 in Alzheimer’s Disease: Cell-Dependent Signalling and Implications for Selective Targeting
AU - Xi Zhao
AU - Youjia Zeng
AU - Zhenyan Song
AU - Jiawei He
AU - Qijun He
AU - Han Lin
AU - Lu Liu
AU - Wenjing Yu
AU - Shaowu Cheng
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209190
UR - https://www.mdpi.com/1422-0067/27/20/9190
AB - 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.
SN - 1422-0067
ER -