Acta Neuropathologica

, Volume 124, Issue 6, pp 809–821 | Cite as

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

  • 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
Original Paper

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.

Keywords

Aβ38 Alzheimer’s disease Familial disease Amyloid Immunohistochemistry 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Maria Luisa Moro
    • 1
  • Giorgio Giaccone
    • 1
  • Raffaella Lombardi
    • 1
  • Antonio Indaco
    • 1
  • Andrea Uggetti
    • 1
  • Michela Morbin
    • 1
  • Stefania Saccucci
    • 1
  • Giuseppe Di Fede
    • 1
  • Marcella Catania
    • 1
  • Dominic M. Walsh
    • 2
  • Andrea Demarchi
    • 3
  • Annemieke Rozemuller
    • 4
  • Nenad Bogdanovic
    • 5
  • Orso Bugiani
    • 1
  • Bernardino Ghetti
    • 6
  • Fabrizio Tagliavini
    • 1
  1. 1.Fondazione IRCCS Istituto Neurologico Carlo Besta, MilanoMilanItaly
  2. 2.Laboratory for Neurodegenerative Research, Brigham and Women’s HospitalHarvard Institute of MedicineBostonUSA
  3. 3.ALS TO2, Ospedale Giovanni BoscoTurinItaly
  4. 4.Department of PathologyVU University Medical CenterAmsterdamThe Netherlands
  5. 5.Division of Clinical Geriatrics, Department for Neurobiology, Caring Sciences and SocietyKarolinska Institutet and Karolinska University HospitalStockholmSweden
  6. 6.Department of Pathology and Laboratory Medicine, Indiana Alzheimer Disease CenterIndiana University School of MedicineIndianapolisUSA

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