Adcyap1r1-driven astrocyte reprogramming attenuates neuroinflammation and promotes dopaminergic neuroprotection in Parkinson’s Disease

Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder globally, is characterized by progressive degeneration of dopaminergic (DA) neurons and sustained neuroinflammatory cascades. Strategies that simultaneously suppress neuroinflammation and protect DA neurons are urgently needed, particularly through targeting astrocytes (As). Building on our previous discovery that combined miR-124 and small molecule interventions synergistically suppress As activation and induce their transdifferentiation into dopaminergic-like neurons, this study identified Adcyap1r1 as a pivotal regulator via RNA-seq analysis. Here, we systematically investigated its cAMP-mediated dual functional roles in neuroinflammatory modulation and DA neuron preservation. TGF-β1-activated neonatal SD rat cortical reactive astrocytes (RAs) were used for Adcyap1r1 overexpression. We assessed astrocyte reactivity, neuroinflammation, neuron-like transition, and cAMP pathway activity in vitro. In MPTP-induced PD mice, AAV-mediated Adcyap1r1 overexpression was targeted to striatal As. Motor function, astrocyte activation, neuroinflammation, and endogenous DA neuron survival in the nigrostriatal system were evaluated through behavioral, histopathological, and molecular analyses. In activated RAs, Adcyap1r1 overexpression significantly attenuated reactivity, reduced pro-inflammatory mediator expression (e.g., COX-2, iNOS), activated cAMP signaling, and promoted the acquisition of a tyrosine hydroxylase-positive (TH + ) neuron-like phenotype. In MPTP-induced PD mice, astrocyte-targeted Adcyap1r1 overexpression in the striatum effectively inhibited astrocytic activation and neuroinflammation, protected endogenous TH + neurons in the nigrostriatal system, and alleviated motor deficits, thereby supporting its DA neuroprotective potential. Our study demonstrates that Adcyap1r1 functions through a cAMP-dependent dual mechanism to suppress astrocyte reactivity and neuroinflammatory cascades, and facilitate the transition of RAs into a DA neuron-like phenotype. This dual regulatory mechanism protects the nigrostriatal DA system and ameliorates motor dysfunction in PD mice, providing a theoretical foundation for developing innovative therapeutic strategies against PD.