5-HT7R Deficiency Alleviates ADP-Heptose-Induced Cognitive Impairment via Inhibiting Ferroptosis and Neuroinflammation in Mice

Abstract

Background

ADP-heptose (ADP-hep), a soluble intermediate in the biosynthesis of lipopolysaccharide in Gram-negative bacteria, is known to trigger inflammation. Our research suggests that 5-hydroxytryptamine receptor 7 (5-HT₇R) could serve as a potential pattern recognition receptor (PRR) for ADP-hep, yet the precise mechanism of ADP-hep's regulation on 5-HT₇R remains unclear.

Aims

Based on the results of mRNA sequencing analysis, this study took ferroptosis of neurons and microglia as a starting point to explore the role and underlying mechanisms of ADP-hep/5-HT₇R signaling in mediating neuroinflammation and cognitive impairment in mice.

Results

We found that 5-HT₇R may act as a potential PRR for ADP-hep and potentially bind to ADP-hep. 5-HT₇R deficiency significantly ameliorated cognitive dysfunction induced by ADP-hep in mice, as well as ferroptosis mediated by the p53/cystine-glutamate antiporter (xCT)/glutathione peroxidase 4 (GPX4) signaling pathway and its associated key markers. Furthermore, 5-HT₇R deficiency inhibited ferroptosis in neurons and M2-type microglia, mitigated the decline in the proportion of M2-type microglia, and subsequently suppressed the inflammatory microenvironment to promote neuronal survival, thereby exerting neuroprotective effects.

Conclusion

In summary, 5-HT₇R deficiency promotes cognitive recovery by alleviating the neuronal and microglial ferroptosis triggered by ADP-hep, subsequently dampening the inflammatory microenvironment to support neuronal viability. These findings provide a novel perspective and approach for the development of innovative therapeutic strategies for the treatment of cognitive impairment-related diseases.