Proteomic insights into early-stage Alzheimer’s disease: Identifying key neuronal proteins impacted by amyloid beta oligomers in an in vitro model

Abstract

Alzheimer’s disease (AD) remains a pressing global health concern, necessitating comprehensive investigations into its underlying molecular mechanisms. While the late-stage pathophysiology of this disease is well understood, it is crucial to examine the role of amyloid beta oligomers (Aβo), which form in the brain during the early stages of disease development. These toxic oligomers could affect neuronal viability and generate oxidative stress in the brain. In this study, we exposed SHSY-5Y cells to Aβo. The increase in intracellular reactive oxygen species and apoptosis observed in Aβo-treated cells mimics the early stages of AD. Comprehensive proteomic profiling identified 2966 differentially expressed proteins, with 123 significantly modulated. Utilizing the NeuroPro database, we identified 80 confirmed AD-related proteins and 43 novel candidates. Seven AD-related proteins with a NeuroPro score ≥ 5 were shortlisted. Furthermore, these proteins are found to be associated with Aβ plaques in AD brains. VGF, LTF, PARP1, and MAOA have been implicated in various mechanisms underlying AD, including synaptic plasticity, iron homeostasis, DNA repair, and neurotransmitter degradation. Our study also revealed the involvement of less-explored proteins like MYH9, CISD1, and SNRNP70, which play critical roles in cytoskeletal dynamics, mitochondrial function, and RNA splicing, respectively. These findings underscore the complex pathophysiology of AD, highlighting potential biomarkers and therapeutic targets for early intervention. The present study advances the understanding of Aβo-induced oxidative stress and neuronal damage, providing a foundation for future research into early-stage AD diagnosis and subsequent treatment strategies.