Identification of the major Aβ1-42-degrading catabolic pathway in brain parenchyma:: Suppression leads to biochemical and pathological deposition

Alzheimer amyloid beta-peptide (A beta) is a physiological peptide constantly anabolized and catabolized under normal conditions. We investigated the mechanism of catabolism by tracing multiple-radiolabeled synthetic peptide injected into rat hippocampus. The A beta(1-42) peptide underwent full degradation through limited proteolysis conducted by neutral endopeptidase (NEP) similar or identical to neprilysin as biochemically analyzed. Consistently, NEP inhibitor infusion resulted in both biochemical and pathological deposition of endogenous A beta(42) in brain. This NEP-catalyzed proteolysis therefore limits the rate of A beta(42) catabolism, up-regulation of which could reduce the risk of developing Alzheimer's disease by preventing A beta accumulation.