Document Detail

APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38.
MedLine Citation:
PMID:  23143229     Owner:  NLM     Status:  MEDLINE    
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.
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
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2012-11-13
Journal Detail:
Title:  Acta neuropathologica     Volume:  124     ISSN:  1432-0533     ISO Abbreviation:  Acta Neuropathol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-28     Completed Date:  2013-06-10     Revised Date:  2013-07-16    
Medline Journal Info:
Nlm Unique ID:  0412041     Medline TA:  Acta Neuropathol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  809-21     Citation Subset:  IM    
Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Milan, Italy.
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MeSH Terms
Aged, 80 and over
Alzheimer Disease / genetics,  metabolism,  pathology*
Amyloid beta-Peptides / metabolism*
Amyloid beta-Protein Precursor / genetics*,  metabolism
Brain / metabolism,  pathology
Cerebral Amyloid Angiopathy / genetics,  metabolism,  pathology*
Middle Aged
Mutation / genetics*
Open Reading Frames
Peptide Fragments / metabolism*
Grant Support
P30 AG 010133/AG/NIA NIH HHS; P30 AG010133/AG/NIA NIH HHS
Reg. No./Substance:
0/Amyloid beta-Peptides; 0/Amyloid beta-Protein Precursor; 0/Peptide Fragments; 0/amyloid beta-protein (1-38)
Erratum In:
Acta Neuropathol. 2013 Mar;125(3):467

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