γ-Secretase inhibition

Development of Alzheimer's disease (AD) pathology appears to be causally related to age-dependent changes in the metabolism of the amyloid-β peptide (Aβ), leading to its enhanced aggregation and deposition.γ-Secretase is a crucial enzyme for the generation of Aβ from the amyloid-β precursor protein and thus represents a valid potential therapeutic target for the treatment or prevention of AD. Enzyme activity has been shown to be dependent on the expression of presenilins and the identification of inhibitors containing transition-state analogue mimics, together with mutagenesis and knockout studies, confirms that presenilins may provide at least a component of the catalytic site for this putative aspartyl protease. Considerable effort has been expended to identify compounds which specifically reduceγ-secretase activity in the central nervous system, and those with the appropriate properties are being utilized in on-going proof-of-concept studies in animals and humans, to determine the extent and duration ofγ-secretase inhibition required to elicit therapeutic benefits.γ-Secretase-mediated substrate cleavage appears to fall into the category of ‘regulated intramembrane proteolysis’. By virtue of its mechanistic similarities, the effects ofγ-secretase inhibitors on proteolysis and signalling through other substrates, such as Notch, has to be determined carefully, since this is likely to impact on the clinically safe dose of these compounds.