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BACE1 is the major β-secretase for generation of Aβ peptides by neurons

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Abstract

Two β-secretases, BACE1 and BACE2, are involved in generation of Alzheimer's disease Aβ peptides1,2,3. We report that secretion of Aβ peptides (Aβ1–40/42 and Aβ11–40/42) is abolished in cultures of BACE1-deficient embryonic cortical neurons, and that whereas both human and murine BACE1 can cleave either human or murine β-amyloid precursor protein (APP) at the +1 site of Aβ, cleavage at the +11 site is species specific. We establish that BACE1 is the principal neuronal protease required to cleave APP at +1 and +11 sites that generate N-termini of Aβ.

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Figure 1: BACE1-deficient neurons fail to secrete Aβ peptides or generate β-CTF.
Figure 2: Altered APP metabolism in BACE1−/− neurons.
Figure 3: Species-specific cleavage of APP at the +11 site of Aβ.

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Acknowledgements

We thank S. Sisodia for CT15 antibodies, T. He, G. Cristostomo, V. Nehus and Y. Xu for technical support, and J. Nathans for reading the manuscript. This work was supported by NIH grant 1P01 AG14248, 2P50 AG05146, and by grants from the Adler Foundation and the Bristol-Myers Squibb Foundation.

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Authors and Affiliations

  1. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Huaibin Cai, Hongjin Wen, David R. Borchelt, Donald L. Price & Philip C. Wong

  2. Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Donald L. Price

  3. Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    David R. Borchelt & Donald L. Price

  4. Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Yanshu Wang

  5. Program in Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Donald L. Price & Philip C. Wong

  6. Ciphergen Biosystems, Fremont, 94555, California, USA

    Diane McCarthy

Authors
  1. Huaibin Cai
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  2. Yanshu Wang
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  3. Diane McCarthy
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  4. Hongjin Wen
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  5. David R. Borchelt
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  6. Donald L. Price
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  7. Philip C. Wong
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Correspondence to Philip C. Wong.

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Cai, H., Wang, Y., McCarthy, D. et al. BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nat Neurosci 4, 233–234 (2001). https://doi.org/10.1038/85064

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  • DOI: https://doi.org/10.1038/85064

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