Dual Role of Exosomes in Parkinson's Disease: Adenine Exerts a Beneficial Effect

Aims: Developing validated treatments for Parkinson's disease (PD) remains a priority for clinicians and researchers. The lack of viable therapies may stem from an incomplete understanding of PD pathogenesis and inadequate therapeutic candidates. The production and transmission of exosomes are gaining recognition in the pathogenesis of neurodegenerative diseases. However, how exosomes affect the pathophysiology of PD has not been well elucidated.

Methods: Here, we investigated the effect of exosomes secreted by rats that were treated with saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) in treating healthy or PD model mice, and we evaluated the efficacy of peripheral and intracranial administration of adenine, which is an exosomal metabolite identified through widely targeted metabolomics.

Results: We found that exosomes derived from the blood of healthy rats alleviated motor dysfunction, dopaminergic neuron loss in the substantia nigra pars compacta and striatum, oxidative injury, and neuroinflammation. Conversely, exosomes from the blood of PD model rats reproduced the behavioral phenotype and pathology of PD in healthy mice. Additionally, peripheral and intracranial administration of adenine ameliorated the motor coordination disorder and dopaminergic neuron loss, and maintained the homeostasis of oxidative stress and neuroinflammation by activating cAMP/PKA signaling in PD.

Conclusion: Together, these findings shed light on the mechanism by which exosomes participate in the pathophysiology of PD by transmitting the metabolite adenine and providing potential therapeutic strategies.

Parkinson's disease; adenine; exosome; metabolite; pathogenicity; therapeutic agent.