Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Aβ42 and decreased Aβ40†‡§
Corresponding Author
Samir Kumar-Singh
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
VIB8—Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, BelgiumSearch for more papers by this authorJessie Theuns
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
Search for more papers by this authorBianca Van Broeck
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
Search for more papers by this authorDaniel Pirici
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
Search for more papers by this authorKrist'l Vennekens
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
Search for more papers by this authorEllen Corsmit
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
Search for more papers by this authorMarc Cruts
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
Search for more papers by this authorBart Dermaut
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
Search for more papers by this authorRong Wang
Department of Human Genetics, Mount Sinai School of Medicine, New York, New York
Search for more papers by this authorCorresponding Author
Christine Van Broeckhoven
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
VIB8—Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, BelgiumSearch for more papers by this authorCorresponding Author
Samir Kumar-Singh
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
VIB8—Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, BelgiumSearch for more papers by this authorJessie Theuns
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
Search for more papers by this authorBianca Van Broeck
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
Search for more papers by this authorDaniel Pirici
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
Search for more papers by this authorKrist'l Vennekens
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
Search for more papers by this authorEllen Corsmit
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
Search for more papers by this authorMarc Cruts
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
Search for more papers by this authorBart Dermaut
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
Search for more papers by this authorRong Wang
Department of Human Genetics, Mount Sinai School of Medicine, New York, New York
Search for more papers by this authorCorresponding Author
Christine Van Broeckhoven
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute of Biotechnology, University of Antwerp, Antwerpen, Belgium
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
VIB8—Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, BelgiumSearch for more papers by this authorCommunicated by Mark Paalman
This article is a US Government work, and, as such, is in the public domain in the United States of America.
Samir Kumar-Singh and Jessie Theuns are joint first authors.
Abstract
The varied ways in which mutations in presenilins (PSEN1 and PSEN2) affect amyloid b precursor protein (APP) processing in causing early-onset familial Alzheimer disease (FAD) are complex and not yet properly understood. Nonetheless, one useful diagnostic marker is an increased ratio of Ab42 to Ab40 (Ab42/Ab40) in patients' brain and biological fluids as well as in transgenic mice and cells. We studied Ab and APP processing for a set of nine clinical PSEN mutations on a novel and highly reproducible enzyme-linked immunosorbent assay (ELISA)-based in vitro method and also sought correlation with brain Ab analyzed by image densitometry and mass spectrometry. All mutations significantly increased Ab42/Ab40 in vitro by significantly decreasing Ab40 with accumulation of APP C-terminal fragments, a sign of decreased PSEN activity. A significant increase in absolute levels of Ab42 was observed for only half of the mutations tested. We also showed that age-of-onset of PSEN1-linked FAD correlated inversely with Ab42/Ab40 (r=–0.89; P=0.001) and absolute levels of Ab42 (r=–0.83; P=0.006), but directly with Ab40 levels (r=0.69; P=0.035). These changes also partly correlated with brain Ab42 and Ab40 levels. Together, our data suggested that Ab40 might be protective by perhaps sequestering the more toxic Ab42 and facilitating its clearance. Also, the in vitro method we describe here is a valid tool for assaying the pathogenic potential of clinical PSEN mutations in a molecular diagnostic setting. Hum Mutat 27(7), 686–695, 2006. Published 2006 Wiley-Liss, Inc.
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