Memory loss is the most profound clinical manifestation in Alzheimer’s disease (AD); however, the molecular mechanisms underlying these deficits are poorly understood. Identification of the molecular pathways involved in the onset of cognitive deficits may lead to the identification of key events in the pathogenesis of AD. Using isobaric tags for relative and absolute quantitation (iTRAQ) and proteomic methods, here we identified learning-induced changes in the hippocampal proteome of non-transgenic (NonTg) and 3 × Tg-AD mice, a widely used animal model of AD. We found that expression of 192 proteins was differentially regulated by learning in NonTg mice. Notably, of these 192 proteins, only 28 were also differentially regulated by learning in 3 × Tg-AD mice, whereas the levels of 164 proteins were uniquely changed in NonTg mice but not in 3 × Tg-AD mice. These data suggest that during learning, 3 × Tg-AD mice fail to differentially regulate 164 proteins. Gene ontology and protein interaction analyses indicated that these proteins were overrepresented in RNA processing, specifically RNA transport, splicing and mRNA translation initiation pathways. These findings suggest that mRNA-processing events that take place during learning and memory are significantly altered in 3 × Tg-AD mice.