Peripheral compartments including blood and cerebrospinal fluid exhibit signals reflecting neuropathological changes in Alzheimer disease (AD).^1,2 In cerebrospinal fluid, these include a decrease in amyloid-β peptide (Aβ) and an increase in total and phosphorylated tau concentrations,³ reflecting amyloid sequestration as plaques and neurofibrillary degeneration, respectively.^4,5 Similarly, while numerous articles suggest that plasma concentrations of several metabolites and proteins might represent responses to neuropathological changes in AD,^6-11 these findings have not been conclusively replicated.¹² A limitation of such studies may be their reliance upon demonstrating changes between affected and unaffected people, a design of study that might identify secondary changes lacking relevance to core disease biology.

Much recent interest has focused on the potential of flavonoids to interact with intracellular signaling pathways such as with the mitogen-activated protein kinase cascade. We have investigated whether the observed strong neurotoxic potential of quercetin in primary cortical neurons may occur via specific and sensitive interactions within neuronal mitogen-activated protein kinase and Akt/protein kinase B (PKB) signaling cascades, both implicated in neuronal apoptosis. Quercetin induced potent inhibition of both Akt/PKB and ERK phosphorylation, resulting in reduced phosphorylation of BAD and a strong activation of caspase-3. High quercetin concentrations (30 μm) led to sustained loss of Akt phosphorylation and subsequent Akt cleavage by caspase-3, whereas at lower concentrations (<10 μm) the inhibition of Akt phosphorylation was transient and eventually returned to basal levels. Lower levels of quercetin also induced strong activation of the pro-survival transcription factor cAMP-responsive element-binding protein, although this did not prevent neuronal damage. O-Methylated quercetin metabolites inhibited Akt/PKB to lesser extent and did not induce such strong activation of caspase-3, which was reflected in the lower amount of damage they inflicted on neurons. In contrast, neither quercetin nor its O-methylated metabolites had any measurable effect on c-Jun N-terminal kinase phosphorylation. The glucuronide of quercetin was not toxic and did not evoke any alterations in neuronal signaling, probably reflecting its inability to enter neurons. Together these data suggest that quercetin and to a lesser extent its O-methylated metabolites may induce neuronal death via a mechanism involving an inhibition of neuronal survival signaling through the inhibition of both Akt/PKB and ERK rather than by an activation of the c-Jun N-terminal kinase-mediated death pathway.