The amyloid-(\beta) peptide (A(\beta)), implicated in the pathogenesis of Alzheimer's disease (AD), is produced through sequential proteolysis of the A(\beta) precursor protein (APP) by (\beta)- and (\gamma)-secretases. Thus, blocking either of these two proteases, directly or indirectly, is potentially worthwhile toward developing AD therapeutics. (\beta)-Secretase is a membrane-tethered pepsin-like aspartyl protease suitable for structure-based design, whereas (\gamma)-secretase is an unusual, heterotetrameric membrane-embedded aspartyl protease. While (\gamma)-secretase inhibitors entered clinical trials first due to their superior pharmacological properties (for example, brain penetration) over (\beta)-secretase inhibitors, it has since become clear that (\gamma)-secretase inhibitors can cause mechanism-based toxicities owing to interference with the proteolysis of another (\gamma)-secretase substrate, the Notch receptor. Strategies for targeting A(\beta) production at the (\gamma)-secretase level without blocking Notch signalling will be discussed. Other strategies utilizing cell-based screening have led to the identification of novel A(\beta) lowering agents that likewise leave Notch proteolysis intact. The mechanism by which these agents lower A(\beta) is unknown, but these compounds may ultimately reveal new targets for AD therapeutics.
