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APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38

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An Erratum to this article was published on 12 February 2013

Abstract

Aβ is the main component of amyloid deposits in Alzheimer disease (AD) and its aggregation into oligomers, protofibrils and fibrils is considered a seminal event in the pathogenesis of AD. Aβ with C-terminus at residue 42 is the most abundant species in parenchymal deposits, whereas Aβ with C-terminus at residue 40 predominates in the amyloid of the walls of large vessels. Aβ peptides with other C-termini have not yet been thoroughly investigated. We analysed Aβ38 in the brains of patients with Aβ deposition linked to sporadic and familial AD, hereditary cerebral haemorrhage with amyloidosis, or Down syndrome. Immunohistochemistry, confocal microscopy, immunoelectron microscopy, immunoprecipitation and the electrophoresis separation of low molecular weight aggregates revealed that Aβ38 accumulates consistently in the brains of patients carrying APP mutations in the Aβ coding region, but was not detected in the patients with APP mutations outside the Aβ domain, in the patients with presenilin mutations or in subjects with Down syndrome. In the patients with sporadic AD, Aβ38 was absent in the senile plaques, but it was detected only in the vessel walls of a small subset of patients with severe cerebral amyloid angiopathy. Our results suggest that APP mutations in the Aβ coding region favour Aβ38 accumulation in the brain and that the molecular mechanisms of Aβ deposition in these patients may be different from those active in patients with familial AD associated with other genetic defects and sporadic AD.

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Acknowledgments

This study was supported by the Italian Ministry of Health (Grant: RF 136 MS to F.T.), the Italian Ministry of Research and Universities (Grant: RM13-MIUR to F.T.) and the National Institute of Heath (Grant: NIH PHS P30 AG 010133 to B.G.). The authors thank Rose M. Richardson, Sonia Spinello and Francesca Cacciatore for the technical help and Dr Giorgio Battaglia and the Unit of Neuroanatomy and Molecular Pathogenesis at IRCCS “C. Besta” Neurological Institute (Milan, Italy) for the use of the Li-COR Odyssey near-infrared imaging system.

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Authors and Affiliations

  1. Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Via Celoria 11, 20133, Milan, Italy

    Maria Luisa Moro, Giorgio Giaccone, Raffaella Lombardi, Antonio Indaco, Andrea Uggetti, Michela Morbin, Stefania Saccucci, Giuseppe Di Fede, Marcella Catania, Orso Bugiani & Fabrizio Tagliavini

  2. Laboratory for Neurodegenerative Research, Brigham and Women’s Hospital, Harvard Institute of Medicine, Boston, MA, USA

    Dominic M. Walsh

  3. ALS TO2, Ospedale Giovanni Bosco, 10154, Turin, Italy

    Andrea Demarchi

  4. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

    Annemieke Rozemuller

  5. Division of Clinical Geriatrics, Department for Neurobiology, Caring Sciences and Society, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

    Nenad Bogdanovic

  6. Department of Pathology and Laboratory Medicine, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA

    Bernardino Ghetti

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  1. Maria Luisa Moro
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Correspondence to Giorgio Giaccone.

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Moro, M.L., Giaccone, G., Lombardi, R. et al. APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38. Acta Neuropathol 124, 809–821 (2012). https://doi.org/10.1007/s00401-012-1061-x

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