Alzheimer’s Disease (AD) is a progressive neurological disorder that gradually deteriorates cognitive abilities and leads to the inability to carry out simple tasks. However, the molecular mechanisms and causes of this disease are still unclear. This research aims to use the proteomic signature of the 5xFAD AD mouse model to identify early changes in protein expression in the AD brain compared to the wild type. Lysates from the cerebral cortex of 3 months-old 5xFAD and wild-type mice were analysed by LC-MS/MS and investigated for protein candidates over- or under- expressed in AD mice compared to wild-type: Cryab, and vGLUT1 were identified as the proteins with the most altered expression in transgenic mice. These candidates were studied in differentiated SH-SY5Y cells upon treatment with amyloid-beta oligomers to mimic AD pathology. This study presents a series of crucial findings such as successful uptake of amyloid beta 1-42 oligomers by differentiated SH-SY5Y cells, the induction of cell apoptosis by Aβ treatment, and for the first time reports the observation of neurite fragmentation in cells treated with Aβ oligomers. Our research investigates molecular mechanisms and suggests new insights into the pathogenesis of AD, whilst highlighting the potential role of Cryab and vGLUT1 in AD pathogenesis, offering valuable insights into synaptic dysfunction and neurodegeneration.