Protease inhibitors as potential disease-modifying therapeutics for Alzheimer’s disease

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Abstract
The current lack of an effective treatment for Alzheimer’s disease (AD) has fuelled an intense search for novel therapies for this neurodegenerative condition. Aberrant production or decreased clearance of amyloid-β peptides is widely accepted to be causative for AD. Amyloid-β peptides are produced by sequential processing of the β-amyloid precursor protein by the two aspartyl-type proteases β-secretase and γ-secretase. Because proteases are generally classified as druggable, these secretases are a centre of attraction for various drug discovery efforts. Although a large number of specific drug-like γ-secretase inhibitors have been discovered, progress towards the clinic has been slowed by the broad substrate specificity of this unusual intramembrane-cleaving enzyme. In particular, the Notch receptor depends on γ-secretase for its signalling function and, thus, γ-secretase inhibition produces distinct phenotypes related to a disturbance of this pathway in preclinical animal models. The main task now is to...