In this context several studies show the presence of Ab oligomers in CSF of AD patients while not in healthy individuals, and also the direct correlation of oligomers with cognitive impairment. Despite all the efforts put on AD research over the past years, there are no effective treatments to prevent, halt or cure the disease. Indeed, there are only four FDA-approved drugs for AD treatment, although they mainly provide a symptomatic improvement and are unable to stop the disease progression. This prompted us to use the therapeutic performance mapping system to explore potential novel indications of marketed drugs to modify the biology of AD. In brief, the TPMS is a topdown systems biology approach with potential applications in drug repositioning. Starting from the clinical effects produced by different therapeutic compounds, we first split them into causative physiological motifs and identified the responsible molecular effectors, which were then 905579-51-3 mapped onto the disease-related cell network. We afterwards established different relationships between drug targets and effector proteins in the network that are used for training a classifier, with capacity for predicting and scoring novel potential indications on AD of totally unrelated drugs. The complete results of this study will be published elsewhere. Interestingly, the TPMS analysis suggested that lansoprazole could act as a strong potential modulator of the processes involved in amyloid-b pathology. Lansoprazole is a proton pump inhibitor drug widely used in the treatment of peptic ulcer disease and other conditions where inhibition of gastric secretion may be beneficial. PPIs are generally well tolerated, and adverse effects are buy PKC412 relatively infrequent. Yet, chronic administration of PPIs is becoming increasingly common, and there is a growing concern about potential unexplored adverse effects from such long-term therapy. In this study, we explore the effects of lansoprazole, and other PPIs, on b-amyloid production in a well-established cellular model of amyloid pathology, with special attention to the effect over the different Ab species. We assess the in vivo relevance of our findings in wild-type and AD triple transgenic mice and we ultimately speculate about the potential mechanisms underlying the observed alterations. Our results reveal that lansoprazole, in addition to its known inhibitory effect on gastric acid production, has an effect on Ab generation. Although the underlying mechanisms remain elusive, our observations show that lansoprazole increases Ab37, Ab40 and Ab42 and lowers Ab38 levels in an AD-like cell model.
