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Although the initial events of Alzheimer's disease (AD) are still not known, it is clear that the disease in its sporadic form results from the combination of genetic and environmental risk factors. Among the latter, behavioral stress has been increasingly recognized as an important factor in the propagation of AD. However, the mechanisms underlying this modulation remain to be fully investigated. Since stress up-regulates the ALOX5 gene product, 5-lipoxygenase (5LO), herein we investigated its role in modulating stress-dependent development of the AD phenotype. To reach this goal, triple transgenic (3xTg) mice and 3xTg genetically deficient for 5LO were investigated after undergoing a restraint/isolation paradigm. In the present paper, we found that 28 days of restraint/isolation stress worsened tau phosphorylation and solubility, increased glycogen synthase kinase 3β activity, compromised long-term potentiation and impaired fear-conditioned memory recall in 3xTg animals, but not in 3xTg animals lacking 5LO (3xTg/5LO−/−). These results highlight the novel functional role that the ALOX5 gene plays in the development of the biochemical, electrophysiological and behavioral sequelae of stress in the AD context. They provide critical support that this gene and its expressed protein are viable therapeutic targets to prevent the onset or delay the progression of AD in individuals exposed to this risk factor.