Overexpression of hippocampal AdipoR1 ameliorates cognitive dysfunction in APP/PS1 mice through inhibiting NLRP3-Mediated neuronal pyroptosis

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder primarily characterized by progressive cognitive dysfunction. Substantial loss of hippocampal neurons is closely associated with irreversible cognitive decline; however, the underlying mechanisms have not yet been fully elucidated. In this study, conditionally overexpressing adiponectin receptor 1 (AdipoR1) in the hippocampus of APP/PS1 transgenic AD mice, we found that it significantly improved learning and memory abilities and effectively mitigated the abnormal loss of hippocampal neurons and dendritic spines. AdipoR1 overexpression primarily maintained neuronal numbers through reducing neuronal death rather than promoting neurogenesis, and this protective effect is closely linked to the inhibition of the neuronal NLRP3 inflammasome, leading to a marked reduction in pyroptosis levels within the hippocampus. Our results demonstrated, for the first time, that AdipoR1 exerted a crucial neuroprotective role in AD pathology through modulating the NLRP3-mediated neuroinflammatory pathway, which might offer new insights into the mechanisms of neuronal loss in AD and suggest that the AdipoR1–NLRP3 signaling axis may serve as a potential therapeutic target for early intervention in AD.