γ-Secretase as a Therapeutic Target in Alzheimer's Disease

gamma-secretase is an intramembranous multi-protein complex that cleaves many type-I proteins with critical roles in neuronal function. In Alzheimer's disease (AD) interest in gamma-secretase comes, in part, from the fact that this complex is responsible for the last cleavage step of the amyloid precursor protein (APP) that generates the amyloid-beta peptide (A beta). A beta represents the primary component of the amyloid plaque, one of the main pathological hallmarks of AD. Over the last years, considerable efforts have been made to develop drugs to reduce A beta production with the aim to slow AD progression. Many inhibitors of this protease have been identified, although the clinical use has been limited by concerns about the possible toxicity of these compounds. gamma-secretase inhibitors have been shown to reduce A beta in vitro and in vivo, but interference with Notch proteolysis causes immunological and gastrointestinal toxicity in animal models. The observation that some nonsteroidal anti-inflammatory drug (NSAID) derivatives are able to specifically lower A beta(42) and the development of inhibitors with Notch-sparing selectivity has revived the interest in gamma-secretase as an attractive target for drug intervention in AD. Despite the fact that all clinical trials with NSAIDs or gamma-secretase modulators in AD have failed to show clinical benefit thus far, the main concern is that the A beta-lowering potency of the tested compounds may be too low. Active efforts are being made to develop compounds able to penetrate into the brain to lower A beta at physiological doses without interfering with the cleavage and function of other critical gamma-secretase substrates. These novel inhibitors and modulators may soon offer hope in the Alzheimer's fight.