Alzheimer's disease: γ-secretase inhibitors

Pathological, genetic, biochemical and pharmacological studies support the hypothesis that brain accumulation of oligomeric species of β-amyloid (Aβ) peptides may cause Alzheimer's disease (AD). Accordingly, compounds that inhibit γ-secretase, the pivotal enzyme that generates Aβ, represent an attractive therapeutic approach for AD. Several classes of potent γ-secretase inhibitors have been synthesized and preclinical studies have indicated that these compounds are able to lower brain Aβ concentrations and, in some cases, to reduce Aβ plaque deposition in transgenic mouse models of AD. Acute administration of γ-secretase inhibitors may attenuate cognitive deficits in transgenic mice but chronic studies are lacking. Unfortunately, γ-secretase inhibitors may cause intestinal goblet cell hyperplasia, thymus atrophy, decrease in lymphocytes and alterations in hair color (effects associated with the inhibition of the cleavage of Notch, a protein involved in cell development and differentiation). At least six γ-secretase inhibitors are being actively studied in humans. Some of them appear to spare Notch cleavage in vitro and are relatively well tolerated in man. Three molecules (LY-450139, BMS-708163 and MK-0752) have been shown to affect Aβ levels in cerebrospinal fluid of humans, a potential biomarker of the disease. The most advanced γ-secretase inhibitor is LY-450139 (semagacestat) that is being studied in a two-year, controlled study in 1500 patients with mild-to-moderate AD. γ-Secretase inhibitors represent a major hope to slow the rate of decline of AD and to modify the natural history of this devastating disease.

Section editor:Leslie Iversen – Department of Pharmacology, University of Oxford, UK