title: APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38.
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.
authors.affiliation: Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Milan, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Moro
authors.forename: Giorgio
authors.initials: G
authors.lastname: Giaccone
authors.forename: Raffaella
authors.initials: R
authors.lastname: Lombardi
authors.forename: Antonio
authors.initials: A
authors.lastname: Indaco
authors.forename: Andrea
authors.initials: A
authors.lastname: Uggetti
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.forename: Stefania
authors.initials: S
authors.lastname: Saccucci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Fede
authors.forename: Marcella
authors.initials: M
authors.lastname: Catania
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.forename: Andrea
authors.initials: A
authors.lastname: Demarchi
authors.forename: Annemieke
authors.initials: A
authors.lastname: Rozemuller
authors.forename: Nenad
authors.initials: N
authors.lastname: Bogdanovic
authors.forename: Orso
authors.initials: O
authors.lastname: Bugiani
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016366:Open Reading Frames; D010446:Peptide Fragments / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078639:amyloid beta-protein (1-38)