ACE2 deficiency alters brain RAS signaling to induce pro-inflammatory microglial remodeling and Worsen Parkinson's disease pathology.

BACKGROUND

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by α-synuclein aggregation and dopaminergic neuron loss. Resident central nervous system (CNS) microglia dynamically switch between pro- and anti-inflammatory states under pathological stress. While cerebral renin-angiotensin system (RAS) participates in PD progression, the molecular connection linking brain RAS to microglial inflammatory remodeling remains undetermined.

METHODS

We combined multi-omics mining of public GEO PD datasets with multiple in vitro and in vivo experiments, including CRISPR-generated ACE2-knockout BV2 microglia, MPTP-treated wild-type and Ace2+/- heterozygous mice, alongside western blot, immunohistochemistry and immunofluorescence, to unravel RAS-mediated microglial regulation in PD.

RESULTS

MPTP robustly triggers pro-inflammatory polarization of midbrain microglia. GSEA analysis of immune-related differential genes revealed enrichment in neuroinflammation, mitochondrial metabolism and antigen presentation pathways. We identified functional hub miRNAs and seven AGTR1-centered hub genes with tight ACE2-AGTR1 interaction. ACE2 deletion disturbs cerebral RAS balance, elevating Ang II and AGTR1 levels. Hyperactivated AGTR1 sequentially activates JAK1-STAT3-ERK, JNK-MAPK, PI3K-AKT-mTOR, Sirt1-FoxO1 and TLR4-Myd88 inflammatory axes, shifting microglia toward a pro-inflammatory phenotype and elevating neuronal injury markers. These data confirm ACE2 deficiency exacerbates PD pathology mainly via overactivated AGTR1 signaling.

CONCLUSION

Disrupted brain RAS homeostasis induces pro-inflammatory microglial remodeling and worsens PD neurodegeneration. This study reveals novel pathogenic mechanisms and identifies promising therapeutic targets for PD treatment.