Neuropharmacology · 2026
Activation and increased hippocampal GPR55 prevents cognitive deficits in male APP/PS1 mice.
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Liang Yusheng, Zhi TianTian, Fan Bing, Wu YangXia, Wu Lei, Xie Zhi, YanYang, Mu RongHao, Wu Xian
Аннотация
BACKGROUND: Alzheimer's disease (AD) is characterized by progressive memory loss and cognitive decline. G protein-coupled receptor 55 (GPR55) has been linked to cognitive regulation, yet its precise role in AD pathogenesis remains unclear.
OBJECTIVES: Here, we investigated the role of GPR55 in AD and its molecular mechanism.
METHODS: This study utilized APP/PS1 and GPR55 knockout (GPR55KO) mice to investigate the role and possible mechanism of GPR55 in AD.
RESULTS: We observed progressive reduction of GPR55 levels in the hippocampus of aging APP/PS1 mice. Conversely, hippocampal GPR55 overexpression rescued cognitive deficits, neuroinflammation, and impairment of synaptic plasticity in APP/PS1 mice. Moreover, GPR55 activation reduced neuronal death and memory impairments in APP/PS1 mice. In addition, aged GPR55KO mice showed cognitive deficits, but hippocampal GPR55 reexpression improved cognition. We also demonstrated that GPR55 activation mitigates Aβ1-42-induced synaptic damage and apoptosis in HT22 cells. Further studies revealed that in both animal and cell models, the levels of P-AKT/AKT and P-GSK3β/GSK3β were significantly decreased, and the level of P-ERK/ERK was markedly increased, while upregulation of GPR55 reversed this trend.
CONCLUSIONS: These results indicate that hippocampal GPR55 may improve cognitive dysfunction by regulating the AKT/GSK3β and ERK signaling pathways, highlighting its crucial role in AD.
OBJECTIVES: Here, we investigated the role of GPR55 in AD and its molecular mechanism.
METHODS: This study utilized APP/PS1 and GPR55 knockout (GPR55KO) mice to investigate the role and possible mechanism of GPR55 in AD.
RESULTS: We observed progressive reduction of GPR55 levels in the hippocampus of aging APP/PS1 mice. Conversely, hippocampal GPR55 overexpression rescued cognitive deficits, neuroinflammation, and impairment of synaptic plasticity in APP/PS1 mice. Moreover, GPR55 activation reduced neuronal death and memory impairments in APP/PS1 mice. In addition, aged GPR55KO mice showed cognitive deficits, but hippocampal GPR55 reexpression improved cognition. We also demonstrated that GPR55 activation mitigates Aβ1-42-induced synaptic damage and apoptosis in HT22 cells. Further studies revealed that in both animal and cell models, the levels of P-AKT/AKT and P-GSK3β/GSK3β were significantly decreased, and the level of P-ERK/ERK was markedly increased, while upregulation of GPR55 reversed this trend.
CONCLUSIONS: These results indicate that hippocampal GPR55 may improve cognitive dysfunction by regulating the AKT/GSK3β and ERK signaling pathways, highlighting its crucial role in AD.