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01-12-2012 | Original Paper

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

Authors: Maria Luisa Moro, Giorgio Giaccone, Raffaella Lombardi, Antonio Indaco, Andrea Uggetti, Michela Morbin, Stefania Saccucci, Giuseppe Di Fede, Marcella Catania, Dominic M. Walsh, Andrea Demarchi, Annemieke Rozemuller, Nenad Bogdanovic, Orso Bugiani, Bernardino Ghetti, Fabrizio Tagliavini

Published in: Acta Neuropathologica | Issue 6/2012

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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Title: APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38
Authors: Maria Luisa Moro
Giorgio Giaccone
Raffaella Lombardi
Antonio Indaco
Andrea Uggetti
Michela Morbin
Stefania Saccucci
Giuseppe Di Fede
Marcella Catania
Dominic M. Walsh
Andrea Demarchi
Annemieke Rozemuller
Nenad Bogdanovic
Orso Bugiani
Bernardino Ghetti
Fabrizio Tagliavini
Publication date: 01-12-2012
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 6/2012
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-012-1061-x

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

Abstract

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