Original Paper

Acta Neuropathologica

, Volume 124, Issue 6, pp 809-821

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

  • Maria Luisa MoroAffiliated withFondazione IRCCS Istituto Neurologico Carlo Besta, Milano
  • , Giorgio GiacconeAffiliated withFondazione IRCCS Istituto Neurologico Carlo Besta, Milano Email author 
  • , Raffaella LombardiAffiliated withFondazione IRCCS Istituto Neurologico Carlo Besta, Milano
  • , Antonio IndacoAffiliated withFondazione IRCCS Istituto Neurologico Carlo Besta, Milano
  • , Andrea UggettiAffiliated withFondazione IRCCS Istituto Neurologico Carlo Besta, Milano
  • , Michela MorbinAffiliated withFondazione IRCCS Istituto Neurologico Carlo Besta, Milano
  • , Stefania SaccucciAffiliated withFondazione IRCCS Istituto Neurologico Carlo Besta, Milano
  • , Giuseppe Di FedeAffiliated withFondazione IRCCS Istituto Neurologico Carlo Besta, Milano
  • , Marcella CataniaAffiliated withFondazione IRCCS Istituto Neurologico Carlo Besta, Milano
    • , Dominic M. WalshAffiliated withLaboratory for Neurodegenerative Research, Brigham and Women’s Hospital, Harvard Institute of Medicine
    • , Andrea DemarchiAffiliated withALS TO2, Ospedale Giovanni Bosco
    • , Annemieke RozemullerAffiliated withDepartment of Pathology, VU University Medical Center
    • , Nenad BogdanovicAffiliated withDivision of Clinical Geriatrics, Department for Neurobiology, Caring Sciences and Society, Karolinska Institutet and Karolinska University Hospital
    • , Orso BugianiAffiliated withFondazione IRCCS Istituto Neurologico Carlo Besta, Milano
    • , Bernardino GhettiAffiliated withDepartment of Pathology and Laboratory Medicine, Indiana Alzheimer Disease Center, Indiana University School of Medicine
    • , Fabrizio TagliaviniAffiliated withFondazione IRCCS Istituto Neurologico Carlo Besta, Milano

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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