Alzheimer's disease, neuropeptides, neuropeptidase, and amyloid-beta peptide metabolism.
Amyloid-beta peptide (Abeta), the pathogenic agent of Alzheimer's disease (AD), is a physiological metabolite in the brain. We have focused our attention and effort on elucidating the unresolved aspect of Abeta metabolism: proteolytic degradation. Among a number of Abeta-degrading enzyme candidates, we used a novel in vivo paradigm to identify a member of the neutral endopeptidase family, neprilysin, as the major Abeta catabolic enzyme. Neprilysin deficiency results in defects in the metabolism of endogenous Abeta 40 and 42 in a gene dose-dependent manner. Our observations suggest that even partial down-regulation of neprilysin activity, which could be caused by aging, can contribute to AD development by promoting Abeta accumulation. Moreover, we discuss the fact that an aging-dependent decline of neprilysin activity, which leads to elevation of Abeta concentrations in the brain, is a natural process that precedes AD pathology. In this Perspective, we hypothesize that neprilysin down-regulation has a role in sporadic AD (SAD) pathogenesis, and we propose that this knowledge be used for developing preventive and therapeutic strategies through use of a G protein-coupled receptor (GPCR).
Saito
Takashi
T
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Takaki
Yoshie
Y
Iwata
Nobuhisa
N
Trojanowski
John
J
Saido
Takaomi C
TC
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D009479:Neuropeptides / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D009479:Neuropeptides; D010450:Endopeptidases