Powering Amyloid Beta Degrading Enzymes: A Possible Therapy for Alzheimer's Disease

The accumulation of amyloid beta (A) in the brain is believed to play a central role in the development and progression of Alzheimer's disease. Revisions to the amyloid cascade hypothesis now acknowledge the dynamic equilibrium in which A exists and the importance of enzymes involved in the production and breakdown of A in maintaining healthy A levels. However, while a wealth of pharmacological and immunological therapies are being generated to inhibit the A-producing enzymes, -site APP cleavage enzyme 1 and -secretase, the therapeutic potential of stimulating A-degrading enzymes such as neprilysin, endothelin-converting enzyme-1 and insulin-degrading enzyme remains relatively unexplored. Recent evidence indicates that increasing A degradation as opposed to inhibiting synthesis is a more effective strategy to prevent A build-up. Therefore A degrading enzymes have become valuable targets of therapy. In this review, we discuss the pathway of A synthesis and clearance along with the opportunities they present for therapeutic intervention, the benefits of increasing the expression/activity of A-degrading enzymes, and the untapped therapeutic potential of enzyme activation.