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Potent amyloidogenicity and pathogenicity of Aβ43

Nature Neuroscience volume 14, pages 1023–1032 (2011)Cite this article

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Abstract

The amyloid-β peptide Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of Aβ43, which is found just as frequently in the brains of affected individuals, remains unresolved. We generated knock-in mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygosity was embryonic lethal, indicating that the mutation involves a loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevated Aβ43, impairment of short-term memory and acceleration of amyloid-β pathology, which accompanied pronounced accumulation of Aβ43 in plaque cores similar in biochemical composition to those observed in the brains of affected individuals. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aβ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with the age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic and abundant in vivo.

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Figure 1: Phenotypic and biochemical characterization of PS1-R278I knock-in mice.
Figure 2: Aβ levels in adult PS1-R278I knock-in mouse brains and MEFs.
Figure 3: Acceleration of Aβ pathology and short-term memory impairment by the R278I knock-in mutation in APP mice.
Figure 4: Aβ40, Aβ42 and Aβ43 in APP × PS1-R278I mice.
Figure 5: Effect of various pathogenic PS1 mutations on Aβ43 production.
Figure 6: Localization of Aβ species in amyloid plaques of APP × PS1-R278I mice.
Figure 7: Mature amyloid plaques in APP × PS1-R278I mice and in vitro aggregation property and neural cell toxicity of Aβ43.
Figure 8: Aβ43 in amyloid plaques in Alzheimer's disease brains.

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Acknowledgements

We thank M.N. Rossor (University College London) for sharing clinical information about the R278I mutation carriers, J.Q. Trojanowski and V.M.-Y. Lee (University of Pennsylvania) for providing postmortem brain tissues, R. Kopan (Washington University) for providing Myc-tagged ΔNotch1 plasmid, A. Takashima (RIKEN Brain Science Institute) for providing antibody to Aph-1, and J. Hardy (University College London) for valuable discussions. This work was supported by research grants from RIKEN Brain Science Institute, the Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labor and Welfare of Japan, the TAKEDA Science Foundation, the Fund for Scientific Research – Flanders (FWO-V), the Interuniversity Attraction Poles program P6/43 of the Belgian Federal Science Policy Office and a Methusalem Excellence Grant of the Flemish Government to C.V.B. N.B receives a FWO-V postdoctoral fellowship.

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  1. Takashi Saito and Takahiro Suemoto: These authors contributed equally to this work.

Authors and Affiliations

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

    Takashi Saito, Takahiro Suemoto, Naomi Mihira, Yukio Matsuba, Per Nilsson, Jiro Takano, Nobuhisa Iwata & Takaomi C Saido

  2. Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, Flanders Interuniversity Institute for Biotechnology, Antwerpen, Belgium

    Nathalie Brouwers, Kristel Sleegers & Christine Van Broeckhoven

  3. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium

    Nathalie Brouwers, Kristel Sleegers & Christine Van Broeckhoven

  4. Faculty of Life Sciences, Doshisha University, Kyoto, Japan

    Satoru Funamoto & Yasuo Ihara

  5. Research Resource Center, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan

    Kazuyuki Yamada

  6. Molecular Neuroscience Research Center, Shiga University of Medical Science, Shiga, Japan

    Masaki Nishimura

  7. Department of Molecular Medicinal Sciences, Division of Biotechnology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Nobuhisa Iwata

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  1. Takashi Saito
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Contributions

This study was jointly designed by T. Saito, T. Suemoto and T.C.S. Experiments were performed by T. Saito, T. Suemoto, N.M., Y.M., K.Y. and S.F. T. Saito, T. Suemoto, S.F., K.Y., P.N., J.T., M.N., N.I., C.V.B., Y.I. and T.C.S. jointly analyzed and interpreted data. N.B., K.S. and C.V.B. identified pathogenic PS1 mutations in patients and families and generated PSEN1 vector constructs for expression studies.

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Correspondence to Takaomi C Saido.

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Saito, T., Suemoto, T., Brouwers, N. et al. Potent amyloidogenicity and pathogenicity of Aβ43. Nat Neurosci 14, 1023–1032 (2011). https://doi.org/10.1038/nn.2858

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