A beta-degrading enzymes in Alzheimer's disease

In Alzheimer's disease (AD) A beta accumulates because of imbalance between the production of A beta and its removal from the brain. There is increasing evidence that in most sporadic forms of AD, the accumulation of A beta is partly, if not in some cases solely, because of defects in its removal-mediated through a combination of diffusion along perivascular extracellular matrix, transport across vessel walls into the blood stream and enzymatic degradation. Multiple enzymes within the central nervous system (CNS) are capable of degrading A beta. Most are produced by neurons or glia, but some are expressed in the cerebral vasculature, where reduced A beta-degrading activity may contribute to the development of cerebral amyloid angiopathy (CAA). Neprilysin and insulin-degrading enzyme (IDE), which have been most extensively studied, are expressed both neuronally and within the vasculature. The levels of both of these enzymes are reduced in AD although the correlation with enzyme activity is still not entirely clear. Other enzymes shown capable of degrading A beta in vitro or in animal studies include plasmin; endothelin-converting enzymes ECE-1 and -2; matrix metalloproteinases MMP-2, -3 and -9; and angiotensin-converting enzyme (ACE). The levels of plasmin and plasminogen activators (uPA and tPA) and ECE-2 are reported to be reduced in AD. Reductions in neprilysin, IDE and plasmin in AD have been associated with possession of APOE epsilon 4. We found no change in the level or activity of MMP-2, -3 or -9 in AD. The level and activity of ACE are increased, the level being directly related to A beta plaque load. Up-regulation of some A beta-degrading enzymes may initially compensate for declining activity of others, but as age, genetic factors and diseases such as hypertension and diabetes diminish the effectiveness of other A beta-clearance pathways, reductions in the activity of particular A beta-degrading enzymes may become critical, leading to the development of AD and CAA.