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

Beta-amyloid (Abeta) 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 Abeta deposition in rodents. Neprilysin (NEP) is the best known target of T/P; however neprilysin knockout results in only modest Abeta increases insufficient to induce deposition. Therefore, other endopeptidases targeted by T/P must be critical for Abeta catabolism. Another candidate is the T/P sensitive membrane metallo-endopeptidase-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 Abeta(42) and Abeta(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 Abeta near the alpha-secretase site (producing Abeta(1-17)>>Abeta(1-16)). These data establish hMMEL as a mediator of Abeta catabolism and raise the possibility of its involvement in the etiology of AD and as a target for intervention.

Simulation of progressive spinal deformities in Duchenne muscular dystrophy using a biomechanical model integrating muscles and vertebral growth modulation.

BACKGROUND: Ninety percent of Duchenne muscular dystrophy patients develop scoliosis in parallel with evident muscular and structural impairment. Altered muscular spinal loads acting on growing vertebrae are likely to promote a self-sustaining spinal deformation process. The purpose of this study was to simulate the effect of asymmetrical fat infiltration of the erector spinae muscles combined with vertebral growth modulation over a period of growth spurt. METHODS: A finite element model of the trunk was built. It integrates (1) longitudinal growth of vertebral bodies and its modulation due to mechanical stresses, (2) muscles and control processes generating muscle recruitment and forces. Three different impairments of the erector spinae muscles were considered and their actions over 12 consecutive cycles representing a span of 12 months were analyzed. FINDINGS: When asymmetrical muscle degeneration was simulated and weaker erector spinae muscles were located on the convex side of the curve, mild scoliosis (Cobb angle of 8-19 degrees ) was induced in the frontal plane and the kyphosis increased from 72 degrees to 110 degrees in all simulations. Those changes were accompanied by a substantial increase of muscle activity in the Rectus Abdominus and Obliquus Internus. INTERPRETATION: Scoliosis as documented in the literature were induced through an asymmetrical activity in the erector spinae muscles and it can be hypothesized that the Rectus Abdominus and Obliquus Internus have a role in maintaining balance and counteracting against spine torsion. This study demonstrated the feasibility of the modeling approach to investigate a musculo-skeletal deformation process based on a neuromuscular deficit.