Activation and increased hippocampal GPR55 prevents cognitive deficits in male APP/PS1 mice.
TL;DR
Results indicate that hippocampal GPR55 may improve cognitive dysfunction by regulating the AKT/GSK3β and ERK signaling pathways, highlighting its crucial role in AD.
Abstract
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 activation levels of P-AKT/AKT and P-GSK3β/GSK3β were significantly decreased, and the activation 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.