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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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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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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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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DOI: https://doi.org/10.1038/nn.2858
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