PERIVASCULAR MACROPHAGES AND MICROGLIA AS KEY PLAYERS IN EXERCISE-INDUCED NEUROIMMUNE REGULATION IN PARKINSON’S DISEASE

Regular physical exercise powerfully regulates brain homeostasis, dampening inflammation, modulating glial activity, strengthening the blood-brain barrier, and enhancing neuroplasticity, cognition, and neuronal resilience. In the context of neurodegenerative disease, physical exercise has been recognized as one of the most promising non-pharmacological strategies for preserving residual brain health.
In experimental parkinsonism, we have previously shown that 4 weeks of daily treadmill exercise restores synaptic plasticity via BDNF-dependent dendritic spine remodeling Based on this evidence, we investigated how intensive exercise modulates neuroinflammation in the dorsolateral striatum and motor cortex. Using α-synuclein-based Parkinson’s disease (PD) models, we found that glial inflammation dynamically mirrors α-synuclein aggregation over time with a peak of reactive, ameboid microglia and persistently elevated astrocytic activation in the dorsolateral striatum.
Here, using an integrated approach combining morphological (IF, Sholl), molecular (RNA Seq, RT-qPCR), and Biochemical (BioPlex citokines multiplex assay) analyses, we demonstrate that physical exercise exerts additional regulatory effects on immune mechanisms within the neurovascular unit (NVU). Notably, we provide that both Major-Histocompatibility-Complex class II (MHCII⁻ and MHCII⁺) perivascular macrophages (PVMs) display exercise-induced reactivity, enhancing their crosstalk with NVU-associated microglia. This interaction is accompanied by increased expression of signaling molecules, such as Spp1 (osteopontin) suggesting that exercise induces an NVU-associated microglial phenotype, promoting phagocytic and M2b-like states. Collectively, these findings identify physical exercise as a potent modulator of neuroimmune interactions, highlighting perivascular macrophages as key players in experimental PD associated with α-synucleinopathy.