γ-Secretase: a complex target for Alzheimer's disease

Data accumulated during the past two decades place amyloid β-peptide (Aβ) 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 Aβ. The γ-secretase protease has deservedly received attention as an attractive drug target, as it is directly involved in Aβ biogenesis and determines the pathogenic potential of Aβ by its heterogeneous catalytic action, generating peptides of various lengths. Despite the complexity of the multi-subunit γ-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.