Perinatal Ethanol Exposure Induces Astrogliosis and Decreases GRP55/PEA-Mediated Neuroprotection in Hippocampal Astrocytes of the 3×Tg Alzheimer’s Animal Model Rodríguez-Pozo, Miguel Pacheco-Sánchez, Beatriz Ben Rabaa, Meriem de Ceglia, Marialuisa Melgar-Locatelli, Sonia De los Santos, Ignacio Rodríguez de Fonseca, Fernando Suárez, Juan Rivera, Patricia Alzheimer’s disease Astrocytes Hippocampus Prenatal ethanol exposure (PEE) alters fetal brain development, potentially increasing the risk of neurodegenerative diseases such as Alzheimer’s disease (AD) later in life. Although glial activation is implicated in AD pathology via cannabinoid and neuroinflammatory signaling, its potential response to PEE in the developing brain and its contribution to AD pathogenesis remain unknown. Using 3×Tg-AD offspring of both sexes born to mothers with PEE, we analyzed astrogliosis, inflammatory markers, and key components of cannabinoid and Ca2+ signaling in primary cultures of hippocampal astrocytes, elements whose dysfunction contributes to neurodegeneration. Our results indicated that PEE increased astrogliosis/inflammatory response (significant elevation of Gfap and Tnfα expression) in hippocampal astrocytes at birth. This neuroinflammation was significantly associated with lower expression of cannabinoid receptors (Cnr1 and Gpr55), and decreased concentrations of the anti-inflammatory lipid PEA in the culture medium, probably due to a deregulated endocannabinoid enzymatic machinery (NAPE-PLD/FAAH ratio). This research provides insights into GRP55/PEA-mediated signaling as a potential hippocampal astrocytic mechanism influenced by maternal ethanol exposure, which may contribute to neurobiological changes associated with increased vulnerability to AD-related pathology. 2025-12-12T09:29:16Z 2025-12-12T09:29:16Z 2025-11-18 journal article Rodríguez-Pozo, M.; Pacheco-Sánchez, B.; Ben Rabaa, M.; de Ceglia, M.; Melgar-Locatelli, S.; Santos, I.; Rodríguez de Fonseca, F.; Suárez, J.; Rivera, P. Perinatal Ethanol Exposure Induces Astrogliosis and Decreases GRP55/PEA-Mediated Neuroprotection in Hippocampal Astrocytes of the 3×Tg Alzheimer’s Animal Model. Int. J. Mol. Sci. 2025, 26, 11154. https://doi.org/10.3390/ijms262211154 https://hdl.handle.net/10481/108746 10.3390/ijms262211154 eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional MDPI