Inhibition of LRRK2 alleviates LPS-induced hippocampal pericyte loss and depressive-like behaviors through suppressing the RIPK1-mediated necroptosis pathway.

Abstract

As essential components of the blood-brain barrier (BBB), pericytes have been implicated in various neurological disorders due to their loss or functional impairment. This study aimed to investigate the role and underlying molecular mechanisms of pericyte loss in the pathogenesis of LPS-induced depressive-like behaviors. We observed that LPS-induced hippocampal pericyte loss was associated with BBB disruption, neuroinflammation, and depressive-like behaviors. Using mouse hippocampal single-cell RNA sequencing data and human brain vascular pericytes microarray data from the GEO database, we identified differentially expressed genes (DEGs) between the LPS-treated and control groups and performed pathway enrichment analysis. Based on this gene signature, we utilized the Connectivity Map (CMap) database to screen for potential therapeutic compounds and identified leucine-rich repeat kinase (LRRK) inhibitors as promising candidates for mitigating LPS-induced pericyte dysfunction. Our results demonstrated that LPS-induced activation of LRRK2 triggered the Receptor-Interacting Protein Kinase 1 (RIPK1)-mediated necroptosis pathway and pericyte loss in human brain vascular pericytes (HBVPs). Immunoprecipitation of LRRK2 revealed that LPS treatment significantly increased the interaction between LRRK2 and activated RIPK1 in HBVPs and hippocampal tissues, and this interaction was abolished by the LRRK2 inhibitors. Furthermore, administration of the LRRK2 inhibitor PF-06447475 effectively suppressed activation of this necroptotic pathway and ameliorated pericyte loss, BBB disruption, microglial activation, neuroinflammation, and depressive-like behaviors in LPS-treated mice. Collectively, our findings indicate that LRRK2 inhibition alleviates LPS-induced hippocampal pericyte loss and depressive-like behaviors primarily through suppression of the RIPK1-mediated necroptosis pathway. These results highlight LRRK2 as a potentially target for the treatment of inflammation-associated depression.