Title: Qualitative changes in human γ-secretase underlie familial Alzheimer's disease
Authors: Szaruga, Maria
Veugelen, Sarah
Benurwar, Manasi
Lismont, Sam
Sepulveda-Falla, Diego
Lleo, Alberto
Ryan, Natalie S
Lashley, Tammaryn
Fox, Nick C
Murayama, Shigeo
Gijsen, Harrie
De Strooper, Bart
Chavez Gutierrez, Lucia # ×
Issue Date: Nov-2015
Publisher: Rockefeller Institute for Medical Research
Series Title: Journal of Experimental Medicine vol:212 issue:12 pages:2003-13
Article number: 10.1084/jem.20150892
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.
ISSN: 0022-1007
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for the Research of Neurodegenerative Diseases
× corresponding author
# (joint) last author

Files in This Item:
File Description Status SizeFormat
Szaruga_2015_JEM.pdfpublished article Published 3940KbAdobe PDFView/Open Request a copy

These files are only available to some KU Leuven Association staff members


All items in Lirias are protected by copyright, with all rights reserved.

© Web of science