Understanding Aβ25-35 peptide altered exosomal proteome and associated pathways linked with the Alzheimer's disease pathogenesis using human neuroblastoma SH-SY5Y Cells.

The central nervous system (CNS) involves a complex interplay of communications between the neurons and various glial cells, which is crucial for brain functions. The major interactomes are exosomes that transmit sundry molecules (DNA, miRNAs, and proteins) between the cells and thus alter cell physiology. Exosomes can act as neuroprotective or neurodegenerative agents depending on the microenvironment of cells secreting them. Therefore, revealing exosome proteome becomes important to understand donor cells' physiology and its effect on the recipient cell. In this study, oxidative stress was induced by Aβ25-35 in the human neuroblastoma SH-SY5Y cells and the protective effects of phytochemical ferulic acid (FA) were evaluated alone and in combination with Aβ25-35 (pre-treated for 3 h before Aβ25-35 exposure) and proteome of their secreted exosomes was analyzed, which was carried out via a high-resolution LC-MS Triple-ToF and further network-based analysis has been carried out using various bioinformatics tools. The proteomic profiling enlightened the multiple roles of exosomes as proteins associated with the various pathways advocate that exosomes can mediate a wide range of effects, from normal physiological processes like synaptic plasticity, neuronal metabolic support, nerve regeneration, DNA repair, axon guidance, and long-term potentiation (LTP) to abnormal pathological processes like inflammatory responses, oxidative stress, apoptosis, and formation of neutrophil extracellular traps (NETs). On comparison, treatment with Aβ25-35 resulted in a significant modulation of the exosomal proteome, promoting pathways associated with neurodegeneration. Conversely, the phytochemical FA displayed a protective effect by effectively countering Aβ25-35-induced oxidative stress responses linked with neurodegeneration, as seen in Alzheimer's disease (AD). Taken together, this study highlights the dual role of exosomes in physiological and pathophysiological neurodegenerative AD, which intricately depend on the particular cellular milieu.