Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition.
Alzheimer amyloid beta-peptide (Abeta) 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 Abeta1-42 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 Abeta42 in brain. This NEP-catalyzed proteolysis therefore limits the rate of Abeta42 catabolism, up-regulation of which could reduce the risk of developing Alzheimer's disease by preventing Abeta accumulation.
Iwata
N
N
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan.
Tsubuki
S
S
Takaki
Y
Y
Watanabe
K
K
Sekiguchi
M
M
Hosoki
E
E
Kawashima-Morishima
M
M
Lee
H J
HJ
Hama
E
E
Sekine-Aizawa
Y
Y
Saido
T C
TC
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006868:Hydrolysis; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D015260:Neprilysin