Advances in the identification of g-secretase inhibitors for the treatment of Alzheimer's disease

), from amyloid precursor protein (APP). APP is believedto be involved in the pathophysiological cascade of AD.Areas covered: This article briefly reviews the profile of g-secretase inhibitorsthat have reached the clinic. The paper reviews studies from the primaryEnglish literature on g-secretase inhibitors published before November 2011,searching through the PubMed database of NCBI by author and the followingkeywords: drugs targeting b-amyloid, g-secretase inhibitors, dementiasyndromes and Alzheimer’s disease.Expert opinion: Studies in both transgenic and non-transgenic animal modelsof AD have indicated that g-secretase inhibitors, administered by the oralroute, are able to lower brain Ab concentrations. However, scanty data areavailable on the effects of these compounds on brain Ab deposition after pro-longed administration. g-Secretase inhibitors may cause significant toxicity inexperimental animals and in humans believed to be associated with the inhi-bition of the cleavage of Notch, a transmembrane receptor involved in regu-lating cell-fate decisions. Unfortunately, two large Phase III clinical trials ofsemagacestat in mild-to-moderate AD patients were prematurely interruptedbecause of the observation of a detrimental cognitive and functional effectsof the drug, possibly due to its lack of selectivity on APP processing. NewAPP-selective g-secretase inhibitors are being developed with the hope ofovercoming the previous setbacks.