Abstract
Alzheimer amyloid β-peptide (Aβ) 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 Aβ1–42 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 Aβ42 in brain. This NEP-catalyzed proteolysis therefore limits the rate of Aβ42 catabolism, up-regulation of which could reduce the risk of developing Alzheimer's disease by preventing Aβ accumulation.
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Acknowledgements
We thank Y. Ihara for supporting and criticizing our work. We also thank H. Uchino and T. Iwatsubo for technical advice and W. Harigaya and Y. Dohzono for secretarial assistance. We also thank M. Ito and the Brain Science Planning Office for support. This work was supported by research grants from RIKEN BSI, Special Coordination Funds for promoting Science and Technology of STA, CREST, Ministry of Health and Welfare, Ministry of Education, Chugai Pharmaceutical Co., Mitsubishi Chemical Co., and Takeda Chemical Industries.
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Iwata, N., Tsubuki, S., Takaki, Y. et al. Identification of the major Aβ1–42-degrading catabolic pathway in brain parenchyma: Suppression leads to biochemical and pathological deposition. Nat Med 6, 143–150 (2000). https://doi.org/10.1038/72237
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DOI: https://doi.org/10.1038/72237
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