Potential novel targets for Alzheimer pharmacotherapy: I. Secretases

Abstract

The prevailing major theory of Alzheimer's disease (AD) is that insoluble amyloid β-peptide (Aβ) found in the cerebral plaques characteristic of the disease is causative or is at least a contributing factor. According to this theory, inhibition of aberrant Aβ production should prevent or at least limit the extent of AD pathophysiology. As three 'secretase' enzymes (α, β and γ) catalyse the proteolytic cleavage of amyloid precursor protein (APP) (the precursor protein of Aβ), one or more secretases have become targets for potential novel AD pharmacotherapy. Secretase inhibitors have been designed and are in various stages of development. The clinical trials of these compounds will, if positive, result in drugs with dramatically better clinical efficacy or, if negative, will force a reassessment of the theory about the role of Aβ in AD.