Qualitative changes in human ?-secretase underlie familial Alzheimer's disease
Por:
Szaruga M., Veugelen S., Benurwar M., Lismont S., Sepulveda-Falla D., Lleo A., Ryan N.S., Lashley T., Fox N.C., Murayama S., Gijsen H., De Strooper B., Chávez-Gutiérrez L.
Publicada:
1 ene 2015
Resumen:
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 ?-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 ?-secretase activity levels, and therefore, loss of overall (endopeptidase) ?-secretase function cannot be an essential part of the pathogenic mechanism. In contrast, impaired carboxypeptidase-like activity (?-secretase dysfunction) is a constant feature in all FAD brains. Significantly, we demonstrate that pharmacological activation of the carboxypeptidase-like ?-secretase activity with ?-secretase modulators alleviates the mutant PSEN pathogenic effects. Most SAD cases display normal endo- and carboxypeptidase- like ?-secretase activities. However and interestingly, a few SAD patient samples display ?-secretase dysfunction, suggesting that ?-secretase may play a role in some SAD cases. In conclusion, our study highlights qualitative shifts in amyloid-ß (Aß) profiles as the common denominator in FAD and supports a model in which the healthy allele contributes with normal Aß products and the diseased allele generates longer aggregation-prone peptides that act as seeds inducing toxic amyloid conformations. © 2015 Szaruga et al.
Filiaciones:
Szaruga M.:
VIB Center for the Biology of Disease, University of Leuven, KU Leuven, Leuven, 3000, Belgium
Center for Human Genetics (CME), Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), Leuven, 3000, Belgium
Veugelen S.:
VIB Center for the Biology of Disease, University of Leuven, KU Leuven, Leuven, 3000, Belgium
Center for Human Genetics (CME), Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), Leuven, 3000, Belgium
Benurwar M.:
VIB Center for the Biology of Disease, University of Leuven, KU Leuven, Leuven, 3000, Belgium
Center for Human Genetics (CME), Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), Leuven, 3000, Belgium
Lismont S.:
VIB Center for the Biology of Disease, University of Leuven, KU Leuven, Leuven, 3000, Belgium
Center for Human Genetics (CME), Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), Leuven, 3000, Belgium
Sepulveda-Falla D.:
Institut für Neuropathologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, 20246, Germany
Neuroscience Group of Antioquia, Faculty of Medicine, University of Antioquia, Medellín, 1226, Colombia
Lleo A.:
Unidad de Memoria, Departamento de Neurología, Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Sant Pau, Barcelona, 08025, Spain
Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Madrid, 28049, Spain
Ryan N.S.:
Dementia Research Centre, University College London, London, WC1N 3AR, United Kingdom
Lashley T.:
Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, University College London, London, WC1N 3AR, United Kingdom
Fox N.C.:
Dementia Research Centre, University College London, London, WC1N 3AR, United Kingdom
Murayama S.:
Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, 173-0015, Japan
Gijsen H.:
Janssen Research and Development Division, Janssen Pharmaceutica NV, Beerse, 2340, Belgium
De Strooper B.:
VIB Center for the Biology of Disease, University of Leuven, KU Leuven, Leuven, 3000, Belgium
Center for Human Genetics (CME), Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), Leuven, 3000, Belgium
Department of Molecular Neuroscience, Institute of Neurology, University College London, London, WC1N 3AR, United Kingdom
Chávez-Gutiérrez L.:
VIB Center for the Biology of Disease, University of Leuven, KU Leuven, Leuven, 3000, Belgium
Center for Human Genetics (CME), Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), Leuven, 3000, Belgium
Bronze
|