O4‐06‐06: 48‐week efficacy and tolerability of treatment with SB‐742457, a novel 5HT6 receptor antagonist, when added on to donepezil in subjects with mild‐to‐moderate Alzheimer's disease (AD)

Abstract

that critically regulate As transport at the BBB and that may be influenced by vascular challenges.Methods: Transverse aortic coarctation (TAC) was performed inmice to induce chronic hypertension. RAGE activationwas analyzed at different time points after TAC and then we usedmicewith genetic ablation of this receptor to disclose whether the phenotype of hypertensive mice recapitulating AD traits was dependent on RAGE activation. Cognitive performancewas evaluated byMorrisWater Maze and brains were analyzed for As deposition.Results:We found that the hypertensive challenge had an early and sustained effect of up-regulation of RAGE expression in cortex and hippocampus, almost exclusively localized in brain vessels. The increased expression of RAGE was preceded by a peak in circulating Advanced Glycation End-products (AGEs) in TAC mice at early time points. Furthermore, a daily oral treatment an inhibitor of AGEs, during the hypertensive challenge, prevented both the early and the sustained increase in RAGE expression. Interestingly, RAGE ablation protected mice from memory impairment and parenchymal As deposition. However, a striking characteristic showed by hypertensive mice lacking RAGE was a strong As accumulation confined to cerebral blood vessels. These results also suggest that RAGE deficiency modulate equilibrium of As between vasculature and cerebral parenchyma via facilitating efflux of As from the brain. Conclusions: Overall we demonstrate that RAGE activation is a crucial pathogenetic event in vascular-related AD, thus suggesting that this therapeutic target could be more successful in the subset of AD patients with vascular related pathology.