Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease

Marta Pera, Daniel Alcolea, Raquel Sánchez-Valle, Cristina Guardia-Laguarta, Martí Colom-Cadena, Nahuai Badiola, Marc Suárez-Calvet, Albert Lladó, Alvaro A. Barrera-Ocampo, Diego Sepulveda-Falla, Rafael Blesa, José L. Molinuevo, Jordi Clarimón, Isidre Ferrer, Ellen Gelpi, Alberto Lleó

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76 Citations (Scopus)


Autosomal-dominant Alzheimer disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studies from families with ADAD have been critical to support the amyloid cascade hypothesis of Alzheimer disease (AD), the basis for the current development of amyloid-based disease-modifying therapies in sporadic AD (SAD). However, whether the pathological changes in APP processing in the CNS in ADAD are similar to those observed in SAD remains unclear. In this study, we measured β-site APP-cleaving enzyme (BACE) protein levels and activity, APP and APP C-terminal fragments in brain samples from subjects with ADAD carrying APP or PSEN1 mutations (n = 18), patients with SAD (n = 27) and age-matched controls (n = 22). We also measured sAPPβ and BACE protein levels, as well as BACE activity, in CSF from individuals carrying PSEN1 mutations (10 mutation carriers and 7 non-carrier controls), patients with SAD (n = 32) and age-matched controls (n = 11). We found that in the brain, the pattern in ADAD was characterized by an increase in APP β-C-terminal fragment (β-CTF) levels despite no changes in BACE protein levels or activity. In contrast, the pattern in SAD in the brain was mainly characterized by an increase in BACE levels and activity, with less APP β-CTF accumulation than ADAD. In the CSF, no differences were found between groups in BACE activity or expression or sAPPβ levels. Taken together, these data suggest that the physiopathological events underlying the chronic Aβ production/clearance imbalance in SAD and ADAD are different. These differences should be considered in the design of intervention trials in AD. © 2012 The Author(s).
Original languageEnglish
Pages (from-to)201-213
JournalActa Neuropathologica
Issue number2
Publication statusPublished - 1 Feb 2013


  • Amyloid precursor protein
  • Autosomal-dominant Alzheimer disease
  • Presenilin
  • β-Amyloid
  • β-Site APP-cleaving enzyme


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