Gamma-secretase: a complex target for Alzheimer's disease

Data accumulated during the past two decades place amyloid beta-peptide (Abeta) at center stage as the main perpetrator in initiating the pathological cascade that eventually leads to Alzheimer's disease. Consequently, significant resources have been allocated to identify and develop treatment strategies that alter the metabolism of Abeta. The gamma-secretase protease has deservedly received attention as an attractive drug target, as it is directly involved in Abeta biogenesis and determines the pathogenic potential of Abeta by its heterogeneous catalytic action, generating peptides of various lengths. Despite the complexity of the multi-subunit gamma-secretase and the lack of structural information, drug discovery research has identified small-molecule compounds that inhibit or modulate activity of this enzyme and some of these have already entered clinical trials.