Aspartic Proteases Involved in Alzheimer's Disease

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Abstract
Alzheimer's disease afflicts every tenth human aged over 65. Despite the dramatic progress that has been made in understanding the disease, the exact cause of Alzheimer's disease is still unknown. Most gene mutations associated with Alzheimer's disease point at the same culprits: amyloid precursor protein and ultimately amyloid β. The enigmatic proteases α‐,β‐, and γ‐secretase are the three executioners of amyloid precursor protein processing, and disruption of their delicate balance is suspected to result in Alzheimer's disease. Significant progress has been made in the selective control of these proteases, regardless of the availability of structural information. Not even the absence of a robust cell‐free assay for γ‐secretase could hamper the identification of nonpeptidic inhibitors of this enzyme for long. Within five years, four distinctly different structural moieties were developed and the first drug candidates are in clinical trials. Unfortunately, selective inhibition of amyloid β formation remains a crucial issue because fundamental fragments of the γ‐secretase complex are important for other signaling events. This problem makes β‐secretase inhibition and α‐secretase induction even more appealing.