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Amyloid β interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer's disease

Nature Neuroscience volume 3, pages 460–464 (2000)Cite this article

Abstract

Amyloid β protein (Aβ) deposition in the brain is a hallmark of Alzheimer's disease (AD). The fibrillar form of Aβ is neurotoxic, although the mechanism of its toxicity is unknown. We showed that conversion of Aβ to the fibrillar form markedly increased binding to specific neuronal membrane proteins, including amyloid precursor protein (APP). Nanomolar concentrations of fibrillar Aβ bound cell-surface holo-APP in cortical neurons. Reduced vulnerability of cultured APP-null neurons to Aβ neurotoxicity suggested that Aβ neurotoxicity involves APP. Thus Aβ toxicity may be mediated by the interaction of fibrillar Aβ with neuronal membrane proteins, notably APP. An Aβ–APP interaction reminiscent of the pathogenic mechanism of prions may thus contribute to neuronal degeneration in AD.

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Figure 1: Binding of amyloid fibrils to neuronal membrane proteins and APP.
Figure 2: Conformational dependence of Aβ binding to APP.
Figure 3: Fibrillar Aβ binds predominantly to membrane-bound holo-APP and, to a much lesser extent, to soluble APP.
Figure 4: Aβ neurotoxicity in primary cortical cultures from APP-wild-type and APP-knockout mice.

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Acknowledgements

This work was supported by NIH grants (NS30352 and NS33325), a grant from Novartis Pharma, Ltd. and a Zenith Award from the Alzheimer's Association to B.A.Y., grants from Conicet and Conicor to A.L., an NIH training grant to Z.Z. and an NIH MRRC Core grant.

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Authors and Affiliations

  1. Department of Neurology, Harvard Medical School and Division of Neuroscience, The Children's Hospital, Enders 260, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Alfredo Lorenzo, Menglan Yuan, Zhuohua Zhang & Bruce A. Yankner

  2. Instituto de Investigación Médica Mercedes y Martín Ferreyra, Casilla de Correo 389, Córdoba, 5000, Argentina

    Alfredo Lorenzo, Jorge Mautino & Francisco Sol Vigo

  3. Preclinical Research, Novartis Pharma Ltd., Basel, CH-4002, Switzerland

    Paolo A. Paganetti, Christine Sturchler-Pierrat, Matthias Staufenbiel & Bernd Sommer

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Correspondence to Bruce A. Yankner.

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Lorenzo, A., Yuan, M., Zhang, Z. et al. Amyloid β interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer's disease. Nat Neurosci 3, 460–464 (2000). https://doi.org/10.1038/74833

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