Sci. Aging Knowl. Environ., 22 January 2003
Vol. 2003, Issue 3, p. pe1
[DOI: 10.1126/sageke.2003.3.pe1]

PERSPECTIVES

Alzheimer's Disease, Neuropeptides, Neuropeptidase, and Amyloid-{beta} Peptide Metabolism

Takashi Saito, Yoshie Takaki, Nobuhisa Iwata, John Trojanowski, and Takaomi C. Saido

Takashi Saito, Yoshie Takaki, Nobuhisa Iwata, and Takaomi C. Saido are at the Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. E-mail: saido{at}brain.riken.go.jp(T.C.S.). John Trojanowski is at the Center for Neurodegenerative Disease Research Institute on Aging and in the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-4283, USA.

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/3/pe1

Key Words: mammalian aging • mutations • aggregates • cell senescence • cell loss • life extension • Alzheimer's disease

Abstract: Amyloid-{beta} peptide (A{beta}), 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 A{beta} metabolism: proteolytic degradation. Among a number of A{beta}-degrading enzyme candidates, we used a novel in vivo paradigm to identify a member of the neutral endopeptidase family, neprilysin, as the major A{beta} catabolic enzyme. Neprilysin deficiency results in defects in the metabolism of endogenous A{beta} 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 A{beta} accumulation. Moreover, we discuss the fact that an aging-dependent decline of neprilysin activity, which leads to elevation of A{beta} 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).

Citation: T. Saito, Y. Takaki, N. Iwata, J. Trojanowski, T. C. Saido, Alzheimer's Disease, Neuropeptides, Neuropeptidase, and Amyloid-{beta} Peptide Metabolism. Science's SAGE KE (22 January 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/3/pe1

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