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

Abstract Beta-amyloid (Aβ) 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 Aβ deposition in rodents. Neprilysin (NEP) is the best known target of T/P; however neprilysin knockout results in only modest Aβ increases insufficient to induce deposition. Therefore, other endopeptidases targeted by T/P must be critical for Aβ catabolism. Another candidate is the T/P sensitive membrane metallo-endopeptidase-like protein (MMEL), a close homolog of neprilysin. The endopeptidase properties of β and γ 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 Aβ42 and Aβ40 by hMMEL-β but not hMMEL-γ. hMMEL-β activity was found at the extracellular surface with no significant secreted activity. hMMEL-γ was not expressed at the extracellular surface. Finally, it was found that hMMEL cleaves Aβ near the α-secretase site (producing Aβ1-17 ≫Aβ1-16 ). These data establish hMMEL as a mediator of Aβ catabolism and raise the possibility of its involvement in the etiology of AD and as a target for intervention.