SENESCENCE-ASSOCIATED MICROGLIAL REACTIVITY IN AGING AND PARKINSONIAN NEURODEGENERATION

Parkinson’s disease (PD) is characterized by α-synuclein (⍺Syn) aggregation and progressive dopaminergic neurodegeneration, with chronically reactive microglia as a contributing factor to this pathological environment. However, the mechanisms behind the persistent reactive state of microglia remain unclear. Emerging evidence suggests that canonical proinflammatory indicators overlap with hallmarks of cellular senescence, raising the question of whether senescent microglia have a role in the progression of PD, particularly given the age-dependent nature of the disease. In this study we investigate the convergence of proinflammatory and senescent features of microglia in aging-associated and parkinsonian dopaminergic neurodegeneration. Using BV-2 murine microglial cells and primary mesencephalic microglia, we examined the expression of senescent marker JunB/AP-1, a transcription factor complex linked to cell-cycle arrest, following exposure to PD-related stimuli (either LPS or ⍺Syn). We further assessed the relationship between ⍺Syn load, dopaminergic loss, and microglial reactivity and senescence in the substantia nigra pars compacta (SNpc) in aged (18-months-old) rats carrying a knock-in of the A53T-mutated SNCA gene. Finally, we evaluated the impact of natural aging on parkinsonian pathology by analyzing the progression of phosphorylated ⍺Syn accumulation, TH⁺neuronal density, neuromelanin abundance, microglial reactivity and senescence markers in the SNpc of different cohorts of naturally aged non-human primates and apes. Together, these results aim to clarify whether microglial senescence contributes to the chronic neuroinflammatory landscape and dopaminergic vulnerability of PD, potentially providing new therapeutic targets.