Biochemical identification of the neutral endopeptidase family member responsible for the catabolism of amyloid beta peptide in the brain.
Amyloid beta peptide (Abeta) is a physiological peptide that is constantly catabolized in the brain. We previously demonstrated that an endopeptidase sensitive to phosphoramidon and thiorphan conducts the initial rate-limiting proteolysis of Abeta in vivo, but the exact molecular identity of the peptidase(s) has remained unknown because of the molecular redundancy of such activity. We analyzed the brain-derived enzyme by means of immuno-depletion and gene disruption, and demonstrate here that neprilysin accounts for the majority of the Abeta-degrading activity. Furthermore, kinetic analysis, giving a K(m) value of 2.8 +/- 0.76 microM, indicated that Abeta(1-42) is a relevant substrate for neprilysin.
Takaki
Y
Y
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan. ytaka@brain.riken.go.jp
Iwata
N
N
Tsubuki
S
S
Taniguchi
S
S
Toyoshima
S
S
Lu
B
B
Gerard
N P
NP
Gerard
C
C
Lee
H J
HJ
Shirotani
K
K
Saido
T C
TC
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002852:Chromatography, Ion Exchange; D006868:Hydrolysis; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D015260:Neprilysin / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D015260:Neprilysin