In Vitro Studies of Flemish, Dutch, and Wild-Type β-Amyloid Provide Evidence for Two-Staged Neurotoxicity
Mutations in the β-amyloid (Aβ) sequence of the amyloid precursor protein gene (APP) present with variable disease phenotypes. While patients with the Dutch APP mutation (E693Q) have predominantly hemorrhagic strokes, Flemish APP (A692G) patients develop both strokes and Alzheimer's disease (AD...
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Format: | Article |
Language: | English |
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Elsevier
2002-11-01
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Series: | Neurobiology of Disease |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996102905292 |
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doaj-9dad1697dacf48c3833b0f7b8bcacb3a |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Samir Kumar-Singh Ann Julliams Rony Nuydens Chantal Ceuterick Christine Labeur Sally Serneels Krist'l Vennekens Peter Van Osta Hugo Geerts Bart De Strooper Christine Van Broeckhoven |
spellingShingle |
Samir Kumar-Singh Ann Julliams Rony Nuydens Chantal Ceuterick Christine Labeur Sally Serneels Krist'l Vennekens Peter Van Osta Hugo Geerts Bart De Strooper Christine Van Broeckhoven In Vitro Studies of Flemish, Dutch, and Wild-Type β-Amyloid Provide Evidence for Two-Staged Neurotoxicity Neurobiology of Disease Alzheimer's disease cerebral amyloid angiopathy tau phosphorylation amyloid β amyloid precursor protein |
author_facet |
Samir Kumar-Singh Ann Julliams Rony Nuydens Chantal Ceuterick Christine Labeur Sally Serneels Krist'l Vennekens Peter Van Osta Hugo Geerts Bart De Strooper Christine Van Broeckhoven |
author_sort |
Samir Kumar-Singh |
title |
In Vitro Studies of Flemish, Dutch, and Wild-Type β-Amyloid Provide Evidence for Two-Staged Neurotoxicity |
title_short |
In Vitro Studies of Flemish, Dutch, and Wild-Type β-Amyloid Provide Evidence for Two-Staged Neurotoxicity |
title_full |
In Vitro Studies of Flemish, Dutch, and Wild-Type β-Amyloid Provide Evidence for Two-Staged Neurotoxicity |
title_fullStr |
In Vitro Studies of Flemish, Dutch, and Wild-Type β-Amyloid Provide Evidence for Two-Staged Neurotoxicity |
title_full_unstemmed |
In Vitro Studies of Flemish, Dutch, and Wild-Type β-Amyloid Provide Evidence for Two-Staged Neurotoxicity |
title_sort |
in vitro studies of flemish, dutch, and wild-type β-amyloid provide evidence for two-staged neurotoxicity |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2002-11-01 |
description |
Mutations in the β-amyloid (Aβ) sequence of the amyloid precursor protein gene (APP) present with variable disease phenotypes. While patients with the Dutch APP mutation (E693Q) have predominantly hemorrhagic strokes, Flemish APP (A692G) patients develop both strokes and Alzheimer's disease (AD). To determine whether these diverse clinical and pathological presentations are due to mutant Aβ or APP, we studied the effect of Flemish, Dutch, and wild-type Aβ/APP on phosphorylation of specific tau epitopes observed in AD. No effect was observed in differentiated SH-SY5Y cells either stably expressing APP or treated with synthetic Aβ12–42. However, we did observe a paradoxical temporal difference in the neurotoxic potential of mutant and wild-type Aβ. While long 24-h incubation at physiological levels of Aβ (2 μM) showed a higher amount of apoptosis for Dutch Aβ, a short 2-h incubation showed elevated apoptosis for Flemish and wild-type Aβ. The altered aggregating properties of Aβ, with Dutch Aβ aggregating faster and Flemish Aβ slower than wild type, elucidated a discrete two-phase Aβ neurotoxicity. We propose here that, at least in vitro, Aβ might be neurotoxic in an initial phase due to its soluble oligomeric or other early toxic Aβ intermediate(s), which is perhaps distinct from the late neurotoxicity incurred by aggregated larger assemblies of Aβ. |
topic |
Alzheimer's disease cerebral amyloid angiopathy tau phosphorylation amyloid β amyloid precursor protein |
url |
http://www.sciencedirect.com/science/article/pii/S0969996102905292 |
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doaj-9dad1697dacf48c3833b0f7b8bcacb3a2021-03-20T04:48:04ZengElsevierNeurobiology of Disease1095-953X2002-11-01112330340In Vitro Studies of Flemish, Dutch, and Wild-Type β-Amyloid Provide Evidence for Two-Staged NeurotoxicitySamir Kumar-Singh0Ann Julliams1Rony Nuydens2Chantal Ceuterick3Christine Labeur4Sally Serneels5Krist'l Vennekens6Peter Van Osta7Hugo Geerts8Bart De Strooper9Christine Van Broeckhoven10Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; Flanders Interuniversity Institute for Biotechnology, Laboratory of Electron Microscopy, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; CNS Discovery Research, Janssen Research Foundation, Beerse, Belgium; Department of Biochemistry, University of Gent, Ghent, Belgium; Laboratory of Neuronal Cell Biology and Gene Transfer, Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Louvain, BelgiumDepartment of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; Flanders Interuniversity Institute for Biotechnology, Laboratory of Electron Microscopy, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; CNS Discovery Research, Janssen Research Foundation, Beerse, Belgium; Department of Biochemistry, University of Gent, Ghent, Belgium; Laboratory of Neuronal Cell Biology and Gene Transfer, Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Louvain, BelgiumDepartment of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; Flanders Interuniversity Institute for Biotechnology, Laboratory of Electron Microscopy, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; CNS Discovery Research, Janssen Research Foundation, Beerse, Belgium; Department of Biochemistry, University of Gent, Ghent, Belgium; Laboratory of Neuronal Cell Biology and Gene Transfer, Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Louvain, BelgiumDepartment of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; Flanders Interuniversity Institute for Biotechnology, Laboratory of Electron Microscopy, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; CNS Discovery Research, Janssen Research Foundation, Beerse, Belgium; Department of Biochemistry, University of Gent, Ghent, Belgium; Laboratory of Neuronal Cell Biology and Gene Transfer, Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Louvain, BelgiumDepartment of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; Flanders Interuniversity Institute for Biotechnology, Laboratory of Electron Microscopy, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; CNS Discovery Research, Janssen Research Foundation, Beerse, Belgium; Department of Biochemistry, University of Gent, Ghent, Belgium; Laboratory of Neuronal Cell Biology and Gene Transfer, Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Louvain, BelgiumDepartment of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; Flanders Interuniversity Institute for Biotechnology, Laboratory of Electron Microscopy, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; CNS Discovery Research, Janssen Research Foundation, Beerse, Belgium; Department of Biochemistry, University of Gent, Ghent, Belgium; Laboratory of Neuronal Cell Biology and Gene Transfer, Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Louvain, BelgiumDepartment of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; Flanders Interuniversity Institute for Biotechnology, Laboratory of Electron Microscopy, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; CNS Discovery Research, Janssen Research Foundation, Beerse, Belgium; Department of Biochemistry, University of Gent, Ghent, Belgium; Laboratory of Neuronal Cell Biology and Gene Transfer, Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Louvain, BelgiumDepartment of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; Flanders Interuniversity Institute for Biotechnology, Laboratory of Electron Microscopy, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; CNS Discovery Research, Janssen Research Foundation, Beerse, Belgium; Department of Biochemistry, University of Gent, Ghent, Belgium; Laboratory of Neuronal Cell Biology and Gene Transfer, Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Louvain, BelgiumDepartment of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; Flanders Interuniversity Institute for Biotechnology, Laboratory of Electron Microscopy, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; CNS Discovery Research, Janssen Research Foundation, Beerse, Belgium; Department of Biochemistry, University of Gent, Ghent, Belgium; Laboratory of Neuronal Cell Biology and Gene Transfer, Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Louvain, BelgiumDepartment of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; Flanders Interuniversity Institute for Biotechnology, Laboratory of Electron Microscopy, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; CNS Discovery Research, Janssen Research Foundation, Beerse, Belgium; Department of Biochemistry, University of Gent, Ghent, Belgium; Laboratory of Neuronal Cell Biology and Gene Transfer, Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Louvain, BelgiumDepartment of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; Flanders Interuniversity Institute for Biotechnology, Laboratory of Electron Microscopy, Born-Bunge Foundation, University of Antwerp, B-2610, Antwerp, Belgium; CNS Discovery Research, Janssen Research Foundation, Beerse, Belgium; Department of Biochemistry, University of Gent, Ghent, Belgium; Laboratory of Neuronal Cell Biology and Gene Transfer, Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Louvain, BelgiumMutations in the β-amyloid (Aβ) sequence of the amyloid precursor protein gene (APP) present with variable disease phenotypes. While patients with the Dutch APP mutation (E693Q) have predominantly hemorrhagic strokes, Flemish APP (A692G) patients develop both strokes and Alzheimer's disease (AD). To determine whether these diverse clinical and pathological presentations are due to mutant Aβ or APP, we studied the effect of Flemish, Dutch, and wild-type Aβ/APP on phosphorylation of specific tau epitopes observed in AD. No effect was observed in differentiated SH-SY5Y cells either stably expressing APP or treated with synthetic Aβ12–42. However, we did observe a paradoxical temporal difference in the neurotoxic potential of mutant and wild-type Aβ. While long 24-h incubation at physiological levels of Aβ (2 μM) showed a higher amount of apoptosis for Dutch Aβ, a short 2-h incubation showed elevated apoptosis for Flemish and wild-type Aβ. The altered aggregating properties of Aβ, with Dutch Aβ aggregating faster and Flemish Aβ slower than wild type, elucidated a discrete two-phase Aβ neurotoxicity. We propose here that, at least in vitro, Aβ might be neurotoxic in an initial phase due to its soluble oligomeric or other early toxic Aβ intermediate(s), which is perhaps distinct from the late neurotoxicity incurred by aggregated larger assemblies of Aβ.http://www.sciencedirect.com/science/article/pii/S0969996102905292Alzheimer's diseasecerebral amyloid angiopathytauphosphorylationamyloid βamyloid precursor protein |