OBJECTIVE In the absence of a cure for Alzheimers disease (AD), development of preventative and therapeutical medications for this disease is particularly encouraged.The flavonoid quercetin has demonstrated protective effects against Aβ-induced toxicity on both neurons and endothelial cells, but whether there is an effect on the neurovascular coupling or the related mechanism is unclear.In the present study, we aimed to investigate the anti-amnesic effects of quercetin and explore the underlying mechanisms.METHODS Mice were given an intracerebroventricular injection of Aβ25-35.Quercetin was dissolved in saline administrated orally for 8 d.The Morris Water Maze (MWM) training began on the 3rd day of quercetin treatment, and mice of each group were trained for five consecutive days; on the 9th day of quercetin treatment, a single probe trial was conducted.The step-through positive avoidance test was performed on the 8th day and 9th day in parallel to the MWM test.The regional cerebral blood flow (rCBF) was monitored before the Aβ25-35 injection and on seven consecutive days.Mice of each group were sacrificed and cerebral cortices were isolated on the 9th day.The effects of quercetin on NVU integrity, microvascular function, cholinergic neuronal changes, and the modification of BNDF, p-ERK and p-CREB levels were tested.RESULTS Our results suggested that oral administrations of quercetin conferred robust anti-amnesic effects and neurovascular coupling protection in Aβ25-35-induced amnesic mice.In these effects, treatment with quercetin at 10 mg· kg-1, 20 mg·kg-1 or 40 mg· kg-1 had a significant group effect on step-through latency and error times during retention trials in the step-through positive avoidance test.Similarly, the escape latency of 20 mg.kg-1 quercetin-administrated mice significantly declined from day 4, and the escape latencies in the quercetin 10 mg· kg-1 and 40 mg·kg-1 groups declined in Day 5.In the quercetin 20 mg.kg-1 group, major components of neurovascular unit were maintained by the increased fluorescent intensities under confocal microscopy, which was related to the preservation of microvascular integrity and the attenuation of serious neuronal loss.Slices had a significant decrease of oxidized HEt signals in the cytosol and in the neurovascular interface.The rCBF value was gradually recovered from 68.58% to 81.90% of the pre-Aβ25-35 basic level from the 6th day.Blood-brain barrier was well protected, and the percentage of cortical microvessels presenting lanthanum ion leakage showed a significant decrease to 38.2%.Further, quercetin showed the effects on the inactivation of neurovascular RAGE signaling pathway both in the microvessels and in the parenchyma.The cholinergic neuronal transmission was also improved, involving an increase of acetylcholine level and the modification of BNDF, p-ERK and p-CREB levels in cerebral cortex.CONCLUSION In summary, with the experimental design and methodology used in the present study, we suggest that quercetin-induced reversal of the impairment of learning and memory performance induced by Aβ25-35 might be partly related to the conservation of cholinergic neuronal regulation of cortical cerebral blood flow and cerebral neurovascular RAGE signaling pathways.These findings suggest that quercetin, a natural flavonoid, could offer an alternative medication for AD.