Objective: To explore the role of neurotrophic signaling pathways in modulating the effect of brain-derived neurotrophic factor (BDNF) on pre-formed fibrils (PFFs)- induced alpha-synuclein (aSyn) aggregation in primary hippocampal neurons. 

Background: Parkinson’s disease (PD) is characterized by neuronal loss and the formation of Lewy bodies, aggregates composed of misfolded aSyn protein. Previous studies have shown the effect of BDNF on the above mentioned  aspects of PD. BDNF is important for neuronal maturation and synaptic plasticity, and its levels inversely correlate with aSyn levels in neurons. The effect of BDNF on the pathological accumulation of aSyn and its molecular mechanisms, however, remain unclear.

Method: Utilizing a PFFs-based aSyn aggregation model in primary hippocampal neurons, as well as immunocytochemistry and a high-content imaging analysis pipeline, we assessed the effects of BDNF on aSyn aggregation. The involvement of key intracellular signaling pathways was examined using pharmacological inhibitors targeting Src kinase (SU6656), MEK1/2 (U0126), and PI3K (LY294002).

Results: BDNF significantly reduces PFFs-induced aSyn accumulation in primary hippocampal neurons, as evidenced by a lower proportion of NeuN-positive aSyn phosphorylated at Serine 129-positive inclusions compared to untreated controls. The protective effect of BDNF was abolished by Src kinase and MEK1/2 inhibitors but remained unaffected by PI-3 kinase inhibition, suggesting that the PI3K/AKT pathway, activated by neurotrophic factors and important for mediating neuronal survival, is not crucial in mediating aSyn aggregation modulation by BDNF. Neuronal viability remained unchanged across all treatment conditions, indicating that the observed effects were not due to differences in cell survival.

Conclusion: Our research highlights the ability of BDNF to attenuate aSyn accumulation in PFFs-based aSyn aggregation model in primary hippocampal neurons, one of the most widely utilized in vitro models of PD. Our findings highlight the importance of growth factor signaling in attenuating protein aggregation, and attest to the potential of BDNF and its complex signaling in the development of disease-modifying therapies.

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/alpha-synuclein-accumulation-attenuating-effect-of-brain-derived-neurotrophic-factor-in-primary-cell-culture-model-of-parkinsons-disease/