Aβ_1-42 peptide toxicity on neuronal cells: A lipidomic study

Currently Alzheimer's Disease (AD) pathological pathways, which lead to cell death and dementia, are not completely well-defined; in particular, the lipid changes in brain tissues that begin years before AD symptoms. Due to the central role of the amyloid aggregation process in the early phase of AD pathogenesis, we aimed at developing a lipidomic approach to evaluate the amyloid toxic effects on differentiated human neuroblastoma derived SH-SY5Y cells. First of all, this work was performed to highlight qualitative and relative quantitative lipid variations in connection with amyloid toxicity. Then, with an open outcome, the study was focused to find out some new lipid-based biomarkers that could result from the interaction of amyloid peptide with cell membrane and could justify neuroblastoma cells neurotoxicity. Hence, cells were treated with increasing concentration of Aβ_1-42 at different times, then the lipid extraction was carried out by protein precipitation protocol with 2-propanol-water (90:10 v/v). The LC-MS analysis of samples was performed by a RP-UHPLC system coupled with a quadrupole-time-of-flight mass spectrometer in comprehensive data - independent SWATH acquisition mode. Data processing was achieved by MS-DIAL. Each lipid class profile in SH-SY5Y cells treated with Aβ_1-42 was compared to the one obtained for the untreated cells to identify (and relatively quantify) some altered species in various lipid classes. This approach was found suitable to underline some peculiar lipid alterations that might be correlated to different Aβ_1-42 aggregation species and to explore the cellular response mechanisms to the toxic stimuli. The in vitro model presented has provided results that coincide with the ones in literature obtained by lipidomic analysis on cerebrospinal fluid and plasma of AD patients. Therefore, after being validated, this method could represent a way for the preliminary identification of potential biomarkers that could be researched in biological samples of AD patients.