Editorial [Hot Topic:Gamma-Secretase Inhibitors and Modulators as a Therapeutic Approach to Alzheimer's disease (Guest Editor: Bruno P. Imbimbo)]

Alzheimer's disease (AD) is the most common cause of dementia. According to the so called “amyloid hypothesis”, the oligomeric forms of a 40-42 aminoacid peptide known as β-amyloid (Aβ), is the main cause of neuronal death in AD. Aβ is the metabolite of a large transmembrane protein called amyloid precursor protein (APP). The last metabolic step that generates Aβ involves the enzymatic intramembrane cleavage of APP by a high-molecular weight complex called γ-secretase. γ-Secretase is formed by at least four proteins: presenilin (PS), nicastrin, anterior pharynx (Aph-1) and presenilin enhancer 2 (Pen-2). Presenilins are of exceptional pathophysiological importance since more than 150 autosomal dominant point mutations are known in these proteins, all of which cause aggressive early-onset AD. These mutations result in increased production of Aβ42, the highly self-aggregating and neurotoxic form of Aβ. Thus, inhibition or modulation of γ-secretase appears to be a logical strategy to decrease Aβ accumulation in AD patients. To fully explore recent advances in the γ-secretase field, Current Topics in Medicinal Chemistry has devoted this entire issue to a review of the structure and function of the γ-secretase complex and summarizes SARs of the main peptidic and nonpeptidic inhibitors of the enzyme. In addition, allosteric modulators of γ-secretase are described since they may represent a safer approach to inhibit Aβ secretion in AD patients. Finally, I have reviewed the γ-secretase inhibitors and modulators that have been selected for development and describe data obtained so far from clinical trials. With a number of companies conducting clinical trials with γ-secretase inhibitors and modulators, it should become clear in the near future whether this attractive target for decreasing Aβ can lead to effective and safe drugs for AD. I would like to express my gratitude to all the Authors for their clear and comprehensive contributions to this special issue of Current Topics in Medicinal Chemistry. Our hope is that this issue will be an informative contribution to the field and will represent a key reference work for those involved in the discovery of γ-secretase inhibitors and modulators.