Metabolic Regulation of Brain Aβ by Neprilysin

Nobuhisa Iwata, Satoshi Tsubuki, Yoshie Takaki, Keiro Shirotani, Bao Lu, Norma P. Gerard, Craig Gerard, Emi Hama, Hahn-Jun Lee, Takaomi C. Saido

doi:10.1126/science.1059946

Metabolic Regulation of Brain Aβ by Neprilysin

DOI Web Site 被引用文献76件

Nobuhisa Iwata

Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi 351-0198 Japan.
Satoshi Tsubuki

Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi 351-0198 Japan.
Yoshie Takaki

Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi 351-0198 Japan.
Keiro Shirotani

Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi 351-0198 Japan.
Bao Lu

Department of Pediatrics and Medicine, Harvard Medical School, Boston, MA 02115, USA.
Norma P. Gerard

Department of Pediatrics and Medicine, Harvard Medical School, Boston, MA 02115, USA.
Craig Gerard

Department of Pediatrics and Medicine, Harvard Medical School, Boston, MA 02115, USA.
Emi Hama

Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi 351-0198 Japan.
Hahn-Jun Lee

Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi 351-0198 Japan.
Takaomi C. Saido

Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi 351-0198 Japan.

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<jats:p>Amyloid β peptide (Aβ), the pathogenic agent of Alzheimer's disease (AD), is a physiological metabolite in the brain. We examined the role of neprilysin, a candidate Aβ-degrading peptidase, in the metabolism using neprilysin gene-disrupted mice. Neprilysin deficiency resulted in defects both in the degradation of exogenously administered Aβ and in the metabolic suppression of the endogenous Aβ levels in a gene dose-dependent manner. The regional levels of Aβ in the neprilysin-deficient mouse brain were in the distinct order of hippocampus, cortex, thalamus/striatum, and cerebellum, where hippocampus has the highest level and cerebellum the lowest, correlating with the vulnerability to Aβ deposition in brains of humans with AD. Our observations suggest that even partial down-regulation of neprilysin activity, which could be caused by aging, can contribute to AD development by promoting Aβ accumulation.</jats:p>