ACE2 Alleviates Microglia Neuroinflammation by RANK-RANKL-OPG Axis in Parkinson's Disease

Parkinson's disease (PD) and osteoporosis are prevalent age-related conditions. Notably, individuals with PD exhibit a markedly elevated risk of osteoporosis and fractures. Osteoprotegerin (OPG), a critical regulator of bone homeostasis, may also influence neuroinflammatory processes. Microglial overactivation, which triggers neuroinflammation, is a key pathogenic mechanism in PD, making the regulation of microglial activity a promising therapeutic approach. Recent studies suggest that Angiotensin-Converting Enzyme-2 (ACE2) is involved in OPG expression and can modulate immune responses. However, the role of OPG in PD progression and whether ACE2 influences microglial function via OPG remain poorly understood. To investigate this interaction, we employed ACE2 knock-in (hACE2) mice and ACE2-transfected BV2 microglial cells. Our findings demonstrate that ACE2 modulation alters the non-classical NF-κB activation pathway by regulating the RANK-RANKL-OPG axis in microglia. This regulation mitigates neuroinflammatory responses and reduces dopaminergic neuronal loss. These results provide insights into the role of the RANK-RANKL-OPG axis in PD and elucidate mechanisms through which ACE2 regulates neuroinflammation.