Aims: α-synuclein is a protein that is highly expressed in brain neurons. Its normal function is still unknown, but it is thought to be crucial to the onset of dementia with Lewy bodies (DLB). As of now, DLB cannot be sufficiently explained by mutations in the α-synuclein protein because there are so few α-synuclein mutations found in DLB. Nevertheless, several studies have revealed that individuals with DLB also co-exhibit Aβ accumulation in the brain, suggesting that Aβ could be involved in α-synuclein neurotoxicity. However, the exact molecular mechanism behind Aβ-induced α-synuclein toxicity is still unknown.Methods: In this work, we conditionally overexpressed α-synuclein in HT-22 cells using a gene-switch model. We co-treated the cells with Aβ to mimic pathology similar to that observed in DLB brains after these cells were able to induce α-synuclein overexpression through the administration of mifepristone (MFP).Results: Our data suggested that Aβ inhibits neuronal insulin signaling, which reduces the efficiency of autophagy and hence suppresses α-synuclein clearance. Furthermore, the neurotoxicity caused by Aβ and α-synuclein can be lessened by a microRNA called miR-302. The mechanism might involve reducing the insulin resistance in neurons caused by Aβ. Conversely, increasing the expression of miR-302 by glucagon-like peptide 1 (GLP-1) signaling in turn reduces the neurotoxicity caused by α-synuclein.Conclusions: We concluded that upregulating miR-302 through increased GLP-1 signaling can mitigate α-synuclein neurotoxicity by improving neuronal insulin signaling, restoring autophagy, and slowing down cellular senescence, which may be beneficial in postponing the advancement of DLB pathology.