Experimental approaches for altering the expression of Abeta‐degrading enzymes

Cerebral clearance of amyloid β‐protein (Aβ) is decreased in early‐onset and late‐onset Alzheimer's disease (AD). Aβ is cleared from the brain by enzymatic degradation and by transport out of the brain. More than 20 Aβ‐degrading enzymes have been described. Increasing the degradation of Aβ offers an opportunity to decrease brain Aβ levels in AD patients. This review discusses the direct and indirect approaches which have been used in experimental systems to alter the expression and/or activity of Aβ‐degrading enzymes. Also discussed are the enzymes' regulatory mechanisms, the conformations of Aβ they degrade, where in the scheme of Aβ production, extracellular release, cellular uptake, and intracellular degradation they exert their activities, and changes in their expression and/or activity in AD and its animal models. Most of the experimental approaches require further confirmation. Based upon each enzyme's effects on Aβ (some of the enzymes also possess β‐secretase activity and may therefore promote Aβ production), its direction of change in AD and/or its animal models, and the Aβ conformation(s) it degrades, investigating the effects of increasing the expression of neprilysin in AD patients would be of particular interest. Increasing the expression of insulin‐degrading enzyme, endothelin‐converting enzyme‐1, endothelin‐converting enzyme‐2, tissue plasminogen activator, angiotensin‐converting enzyme, and presequence peptidase would also be of interest. Increasing matrix metalloproteinase‐2, matrix metalloproteinase‐9, cathepsin‐B, and cathepsin‐D expression would be problematic because of possible damage by the metalloproteinases to the blood brain barrier and the cathepsins' β‐secretase activity. Many interventions which increase the enzymatic degradation of Aβ have been shown to decrease AD‐type pathology in experimental models. If a safe approach can be found to increase the expression or activity of selected Aβ‐degrading enzymes in human subjects, then the possibility that this approach could slow the AD progression should be examined in clinical trials. Aβ monomers, oligomers, and fibrils can be degraded by a variety of enzymes both extracellularly and intracellularly, as indicated. The cerebral expression of some of the enzymes decreases in Alzheimer's disease, while others are unchanged or increased. Many approaches have been used to alter the expression and/or activity of these enzymes in experimental systems, and some of these approaches decreas