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

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

  • Int Immunopharmacol. 2026 Apr 15:175:116414. doi: 10.1016/j.intimp.2026.116414.
Jun Liu 1,  Dan-Hong Xu 2,  Xiao-Yong Zhang 2,  Hui Sheng 2,  Jun-Hui Zhan 3,  Yi-Ting You 1,  Xiao-Yan Zhu 4,  Yu-Jian Liu 5
Affiliations

Affiliations

  • 1 School of Exercise and Health, Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China.
  • 2 Department of Physiology, Naval Medical University, Shanghai 200433, China.
  • 3 School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
  • 4 Department of Physiology, Naval Medical University, Shanghai 200433, China. Electronic address: [email protected].
  • 5 School of Exercise and Health, Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China. Electronic address: [email protected].
PMID: 41740343 DOI: 10.1016/j.intimp.2026.116414
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.

Keywords

BBB; Depressive-like behaviors; LRRK2; Pericyte; RIPK1-mediated necroptosis.

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