MPP+ induces α-synuclein oligomerization and neurite impairment by disrupting mitochondrial function and Akt signaling, with apigenin emerging as a potential neuroprotective agent.

Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by α-synuclein accumulation and mitochondrial impairment. Mitigating α-synuclein aggregation and mitochondrial dysfunction are prominent strategies in PD treatment. Apigenin, a dietary flavonoid, exhibits anti-inflammatory neuroprotective potential in PD models. However, it is still unclear whether apigenin possesses any impact on α-synuclein aggregation and mitochondrial dysfunction. Here, the effects and underlying mechanism of apigenin were investigated using MPP+-induced PD-like pathology in SH-SY5Y cells. Our results showed that apigenin significantly ameliorated neuronal apoptosis through inhibiting Bax/caspase-3 pathway and activating Bcl-2, increased size of SH-SY5Y neurospheres, and attenuated the levels of α-synuclein oligomers in MPP+-treated cells. Furthermore, apigenin improved MPP+-induced neurite damage as indicated by increased neurite length and expression of tyrosine hydroxylase (TH), growth associated protein 43 (GAP-43) and post-synaptic density protein (PSD-95). Increased ROS levels, depleted ATP levels, and decreased mitochondrial membrane potential and p-Drp1 expression in MPP+-treated cells were alleviated by apigenin. Further studies revealed that apigenin could enhance Akt activity. By using a specific Akt inhibitor, perifosine, the effects of apigenin on preventing MPP+-triggered PD pathologies were eliminated. Together, this work demonstrated that apigenin exerted neuroprotection by mitigating α-synuclein oligomers, neurite damage, mitochondrial dysfunction and neuronal apoptosis via Akt-dependent mechanism.