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Identification of the major Aβ1–42-degrading catabolic pathway in brain parenchyma: Suppression leads to biochemical and pathological deposition

Nature Medicine volume 6, pages 143–150 (2000)Cite this article

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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Figure 1: Experimental scheme.
Figure 2: Profiles of in vivo 3H/14C-Aβ1–42 proteolysis.
Figure 3: Two-dimensional HPLC separation of the catabolic intermediate and its aggregation property
Figure 4: Effect of protease inhibitors on 3H/14C-Aβ1–42 degradation.
Figure 5: Proteolysis of 3H/14C-Aβ1–42 by isolated brain NEP.
Figure 6: Immunohistochemistry of rat brain treated with thiorphan.

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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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Authors and Affiliations

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

    Nobuhisa Iwata, Satoshi Tsubuki, Yoshie Takaki, Kaori Watanabe, Misaki Sekiguchi, Emi Hosoki, Hahn-Jun Lee, Emi Hama, Yoko Sekine-Aizawa & Takaomi C. Saido

  2. Department of Neuropathology, Faculty of Medicine University of Tokyo, Bunkyo-ku, Tokyo, 113-0033

    Maho Kawashima-Morishima

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Correspondence to Takaomi C. Saido.

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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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