Amyloid-beta (A beta) peptides accumulate in the brain and initiate a cascade of pathologic events in Alzheimer's disease. The receptor for advanced glycation end products (RAGE) has been implicated to mediate A beta-induced perturbations in the neurovascular unit (NVU). We demonstrated that pinocembrin exhibits neuroprotection through inhibition of the A beta and/or RAGE pathway, but the therapeutic role and mechanism involved are not ascertained. Here, we report that a 3-month treatment with pinocembrin prevents the cognition decline in APP/PS1 transgenic mice without altering A beta burden and oxidative stress. Instead, pinocembrin is effective in conferring neurovascular protection through maintenance of neuropil ultrastructure, reduction of glial activation and levels of inflammatory mediators, preservation of microvascular function, improving the cholinergic system by conserving the ERK-CREB-BDNF pathway, and modulation of RAGE-mediated transduction. Furthermore, in an in vitro model, pinocembrin provides the NVU protection against fibrillar A beta(1-42), accompanied by regulation of neurovascular RAGE pathways. Our findings indicate that pinocembrin improves cognition, at least in part, attributable to the NVU protection, and highlights pinocembrin as a potential therapeutic strategy for the prevention and/or treatment of Alzheimer's disease. (C) 2014 Elsevier Inc. All rights reserved.