Intracerebroventricular infusion of exercise donor plasma exosomes induces molecular changes indicating exercise-like adaptations in basal ganglia cells of older male rats.

Chronic moderate aerobic exercise promotes health in older adults and provides neuroprotection to patients with neurodegenerative diseases, most notably Parkinson's disease (PD). Exosomes are small extracellular vesicles that facilitate interorgan communication. During exercise, they are selectively packaged with bioactive molecules termed "exerkines" and released into the blood. Exosomes protect their exerkine cargo, including DNA, RNA, and proteins, and facilitate their interorgan transit. Since aging is the primary risk factor for common neurodegenerative disorders, including PD, in this study, we explored the potential to transfer exercise-induced adaptive changes from active donors to sedentary recipients via exosomal factors in aged rats. We hypothesized that infusing exosomes from exercised donors could induce exercise-like changes in the brains of sedentary recipients. Aged sedentary rats fitted with an intracerebroventricular cannula were infused with plasma exosomes from exercised or sedentary donors. The basal ganglia were removed for single-nuclei RNA sequencing and immunoblotting. When compared to controls, rats that received exosomes from exercised donors had lower gene expression associated with activated microglia, as evidenced by decreased mTOR signaling and oxidative phosphorylation. Parkinson's disease signaling pathways were most significantly downregulated in astrocytes, while calcium, cyclic adenosine monophosphate (cAMP), and mitogen-activated protein kinase (MAPK) signaling pathways were downregulated in microglia. Neuronal activity was mixed; for example, in dopaminergic neurons of the substantia nigra, neuroactive ligand-receptor interaction and calcium signaling pathways were upregulated, while oxidative phosphorylation was downregulated. The levels of exercise-associated peptides brain-derived neurotrophic factor (BDNF) and irisin were also elevated. This proof of concept study demonstrates that the infusion of exosomes from the plasma of exercised donors elicits cell-specific molecular changes consistent with exercise-induced adaptations in the brains of sedentary recipients.