Native Mass Spectrometry-Centric Approaches Revealed That Neuropeptides Frequently Interact with Amyloid-β

Amyloid-beta (A beta) aggregates are recognized as initiators of Alzheimer's disease, and their interaction with the nervous system contributes to the progression of neurodegeneration. Herein, we investigated the frequency at which neuropeptides interact with A beta and affect the aggregation kinetics and cytotoxicity of A beta. To this end, we established a native mass spectrometry (MS)-centric workflow for screening A beta-interacting neuropeptides, and six out of 12 neuropeptides formed noncovalent complexes with A beta species in the MS gas phase. Thioflavin-T fluorescence assays and gel separation indicated that leptin and cerebellin decreased A beta aggregation, whereas kisspeptin increased this process. In addition, leptin and cerebellin attenuated A beta-induced cytotoxicity, which was independent of the influence of metal ions. Leptin can chelate copper from copper-bound A beta species, reducing the cytotoxicity caused by the aggregation of A beta and metal ion complexes. Overall, our study demonstrated that neuropeptides frequently interact with A beta and revealed that leptin and cerebellin are potential inhibitors of A beta aggregation, providing great insight into understanding the molecular mechanism of A beta interacting with the nervous system and facilitating drug development.