AMPK activation mitigates α-synuclein pathology and dopaminergic degeneration in cellular and mouse models of Parkinson's disease

Abstract

Parkinson's disease (PD) is characterized by oxidative stress, mitochondrial dysfunction, and pathological accumulation of p-α-Synuclein (p-α-Syn). AMP-activated protein kinase (AMPK) has emerged as a regulator of cellular energy homeostasis, yet its role in PD pathology remains unclear. Here, we examined the effects of AMPK activation in SH-SY5Y neuroblastoma cells and in an MPTP-induced PD mouse model. In both undifferentiated and retinoic acid-differentiated SH-SY5Y cells exposed to 6-hydroxydopamine (6-OHDA), pharmacological AMPK activation with AICAR reduced reactive oxygen species (ROS) production and p-α-Syn aggregation. These effects were associated with enhanced mitophagy, increased lysosomal degradation, and stimulation of mitochondrial biogenesis, collectively restoring mitochondrial integrity and improving dopaminergic features. In vivo, AICAR treatment attenuated nigrostriatal dopaminergic degeneration in MPTP-exposed mice, reduced p-α-Syn accumulation, and preserved tyrosine hydroxylase expression. Moreover, systemic cytokine analysis revealed that AMPK activation suppressed IL-6-mediated inflammation, while modulating IL-1β levels in a context-dependent manner. These results demonstrate that AMPK activation mitigates α-synuclein pathology, preserves mitochondrial function, and protects dopaminergic neurons in both cellular and animal PD models. Our findings support AMPK as a potential therapeutic target for disease modification in PD.

Keywords: AMP-Activated protein kinase; Mitochondrial homeostasis; Oxidative stress; Parkinson's disease; p-α-Syn.