Human membrane metallo-endopeptidase-like protein degrades both beta-amyloid 42 and beta-amyloid 40

Beta-amyloid (A beta) degrading endopeptidases are thought to protect against Alzheimer's disease (AD) and are potentially therapeutic. Of particular interest are endopeptidases that are blocked by thiorphan and phosphoramidon (T/P), as these inhibitors rapidly induce A beta deposition in rodents. Neprilysin (NEP) is the best known target of T/P; however neprilysin knockout results in only modest A beta increases insufficient to induce deposition. Therefore, other endopeptidases targeted by TIP must be critical for A beta catabolism. Another candidate is the T/P sensitive membrane metalloendopeptidase-like protein (MMEL), a close homolog of neprilysin. The endopeptidase properties of beta and gamma splice forms of human MMEL were determined in HEK293T cells transduced with the human cDNAs for the two splice forms; this showed degradation of both A beta(42) and A beta(40) by hMMEL-beta but not hMMEL-gamma. hMMEL-beta activity was found at the extracellular surface with no significant secreted activity. hMMEL-gamma was not expressed at the extracellular surface. Finally, it was found that hMMEL cleaves A beta near the alpha-secretase site (producing A beta(1-17) >> A beta(1-16)). These data establish hMMEL as a mediator of A beta catabolism and raise the possibility of its involvement in the etiology of AD and as a target for intervention. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.