Qualitative changes in human γ-secretase underlie familial Alzheimer's disease
Szaruga, Maria (Katholieke Universiteit te Leuven (1970- ))
Veugelen, Sarah (Katholieke Universiteit te Leuven (1970- ))
Benurwar, Manasi (Katholieke Universiteit te Leuven (1970- ))
Lismont, S. (Katholieke Universiteit te Leuven (1970- ))
Sepulveda-Falla, Diego (Universidad de Antioquia)
Lleó, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Ryan, Natalie S. (University College London)
Lashley, Tammaryn (University College London)
Fox, Nick C. (University College London)
Murayama, Shigeo (Tokyo Metropolitan Institute of Gerontology)
Gijsen, Harrie (Janssen Pharmaceutica NV (Bèlgica))
De Strooper, Bart (University College London)
Chávez-Gutiérrez, Lucía (Katholieke Universiteit te Leuven (1970- ))
Universitat Autònoma de Barcelona. Departament de Medicina

Date:	2015
Abstract:	Presenilin (PSEN) pathogenic mutations cause familial Alzheimer's disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other to cause neurodegeneration remains unclear. In this study, we assessed γ-secretase activity in brain samples from 15 nondemented subjects, 22 FAD patients harboring nine different mutations in PSEN1, and 11 sporadic AD (SAD) patients. FAD and control brain samples had similar overall γ-secretase activity levels, and therefore, loss of overall (endopeptidase) γ-secretase function cannot be an essential part of the pathogenic mechanism. In contrast, impaired carboxypeptidase-like activity (γ-secretase dysfunction) is a constant feature in all FAD brains. Significantly, we demonstrate that pharmacological activation of the carboxypeptidase-like γ-secretase activity with γ-secretase modulators alleviates the mutant PSEN pathogenic effects. Most SAD cases display normal endo- and carboxypeptidase- like γ-secretase activities. However and interestingly, a few SAD patient samples display γ-secretase dysfunction, suggesting that γ-secretase may play a role in some SAD cases. In conclusion, our study highlights qualitative shifts in amyloid-β (Aβ) profiles as the common denominator in FAD and supports a model in which the healthy allele contributes with normal Aβ products and the diseased allele generates longer aggregation-prone peptides that act as seeds inducing toxic amyloid conformations.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials i que es distribueixin sota la mateixa llicència que regula l'obra original. Cal que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Adult ; Aged ; Alzheimer Disease ; Amyloid ; Amyloid beta-Protein Precursor ; Amyloid Precursor Protein Secretases ; Animals ; Blotting, Western ; Brain ; Carboxypeptidases ; Cells, Cultured ; Female ; Humans ; Male ; Mice, Knockout ; Middle Aged ; Mutation ; Presenilin-1
Published in:	The journal of experimental medicine, Vol. 212 Núm. 12 (16 2015) , p. 2003-2013, ISSN 1540-9538

DOI: 10.1084/jem.20150892
PMID: 26481686

11 p, 1.4 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles