Selective amyloid-beta lowering agents

作者：Wolfe Michael S^*

来源：BMC Neuroscience, 2008, 9: S4.

DOI：10.1186/1471-2202-9-S2-S4

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.

• 出版日期2008-12-3