Qualitative changes in human γ-secretase underlie familial Alzheimer's disease.
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.
VIB Center for the Biology of Disease, University of Leuven (KU Leuven), 3000 Leuven, Belgium Center for Human Genetics (CME) and Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), 3000 Leuven, Belgium.
Maria
M
Szaruga
VIB Center for the Biology of Disease, University of Leuven (KU Leuven), 3000 Leuven, Belgium Center for Human Genetics (CME) and Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), 3000 Leuven, Belgium.
Sarah
S
Veugelen
VIB Center for the Biology of Disease, University of Leuven (KU Leuven), 3000 Leuven, Belgium Center for Human Genetics (CME) and Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), 3000 Leuven, Belgium.
Manasi
M
Benurwar
VIB Center for the Biology of Disease, University of Leuven (KU Leuven), 3000 Leuven, Belgium Center for Human Genetics (CME) and Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), 3000 Leuven, Belgium.
Sam
S
Lismont
Institut für Neuropathologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany Neuroscience Group of Antioquia, Faculty of Medicine, University of Antioquia, Medellín 1226, Colombia.
Diego
D
Sepulveda-Falla
Unidad de Memoria, Departamento de Neurología, Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Sant Pau, 08025 Barcelona, Spain Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain.
Alberto
A
Lleo
Dementia Research Centre, Institute of Neurology, University College London, London WC1N 3AR, England, UK.
Natalie S
NS
Ryan
Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3AR, England, UK.
Tammaryn
T
Lashley
Dementia Research Centre, Institute of Neurology, University College London, London WC1N 3AR, England, UK.
Nick C
NC
Fox
Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
Shigeo
S
Murayama
Janssen Research and Development Division, Janssen Pharmaceutica NV, 2340 Beerse, Belgium.
Harrie
H
Gijsen
VIB Center for the Biology of Disease, University of Leuven (KU Leuven), 3000 Leuven, Belgium Center for Human Genetics (CME) and Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), 3000 Leuven, Belgium Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3AR, England, UK Lucia.ChavezGutierrez@cme.vib-kuleuven.be Bart.DeStrooper@cme.vib-kuleuven.be.
Bart
B
De Strooper
VIB Center for the Biology of Disease, University of Leuven (KU Leuven), 3000 Leuven, Belgium Center for Human Genetics (CME) and Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), 3000 Leuven, Belgium Lucia.ChavezGutierrez@cme.vib-kuleuven.be Bart.DeStrooper@cme.vib-kuleuven.be.
Lucía
L
Chávez-Gutiérrez
D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002268:Carboxypeptidases / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D002268:Carboxypeptidases