IRF1 ameliorates synaptic dysfunction through the modulation of O-GlcNAcylation on GluN1 subunit of NMDAR.

Abstract

Background: Synaptic dysfunction, which occurs before the formation of amyloid plaques (Aβ) and neurofibrillary tangles (NFTs), is strongly associated with cognitive deficits and represents major early clinical features of Alzheimer's disease (AD). Abnormal NMDAR signaling emerges as a noticeable feature of synaptic dysfunctions in AD. Nonetheless, the underlying mechanisms of NMDAR dysfunctions remain unclear.

Methods: 3xTg-AD mice were injected with AAV-IRF1. Cognitive function was assessed using behavioral tests, while biochemical and immunofluorescence analyses were conducted to evaluate the protein levels of IRF-1, OGA, subunits of NMDAR, O-GlcNAcylation of NMDAR subunits, and internalization of NMDA receptors. Synaptic alterations in the hippocampus were detected by electrophysiology and Golgi staining.

Results: In the present study, we demonstrate that Interferon Regulatory Factor-1 (IRF-1), which is deficient in the brain of individuals with Alzheimer's disease (AD), negatively regulates the O-GlcNAcylation levels of GluN1 through transcriptional regulation of the human OGA gene. Furthermore, IRF-1 may influence trafficking of NMDARs, thereby affecting dendritic spine density and synaptic plasticity, and ultimately improving the learning and memory of 3xTg-AD mice.

Conclusion: Our results indicate that IRF1 can improve the cognitive function of 3xTg-AD mice by regulating the O-GlcNAcylation of GluN1, offering evidence that IRF-1 could serve as a novel therapeutic target for treating synaptic dysfunction in Alzheimer's diseases.