BACKGROUND: Plant secondary metabolites may induce adaptive cellular stress-responses in a variety of cells including neurons at the sub-toxic doses ingested by humans. Such 'neurohormesis' phenomenon, activated by flavonoids such as quercetin or rutin, may involve cell responses driven by modulation of signaling pathways which are responsible for its neuroprotective effects. PURPOSE: We attempt to explore the molecular mechanisms involved in the neurohormetic responses to quercetin and rutin exposure, in a SH-SY5Y cell line which stably overexpresses the amyloid precursor protein (APP) Swedish mutation, based on a biphasic concentration-response relationship for cell viability. METHODS: We examined the impact of both natural compounds, at concentrations in its hormetic range on the following cell parameters: chymotrypsin-like activity of the proteasome system; PARP-1 protein levels and expression and caspase activation; APP processing; and the main endogenous antioxidant enzymes. RESULTS: Proteasome activities following quercetin or rutin treatment were significantly augmented in comparison with non-treated cells. Activity of caspase-3 was significantly attenuated by treatment with quercetin or rutin. Modest increased levels of PARP-1 protein and mRNA transcripts were observed in relation to the mild increase of proteasome activity. Significant reductions of the full-length APP and sAPP protein and APP mRNA levels were related to significant enhancements of α-secretase ADAM-10 protein and mRNA transcripts and significant increases of BACE processing in cells exposed to rutin. Furthermore, quercetin or rutin treatment displayed an overall increase of the four antioxidant enzymes. CONCLUSIONS: The upregulation of the proteasome activity observed upon quercetin or rutin treatment could be afforded by a mild increased of PARP-1. Consequently, targeting the proteasome by quercetin or rutin to enhance its activity in a mild manner could avoid caspase activation. Moreover, it is likely that APP processing of cells upon rutin treatment is mostly driven by the non-amyloidogenic pathway leading to a putative reduction of βA production. Overall induction of endogenous antioxidant enzymes under quercetin or rutin treatments of APPswe cells might modulate its proteasome activity. We might conclude that quercetin and rutin might exert a neurohormetic cell response affecting various signaling pathways and molecular networks associated with modulation of proteasome function.