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Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability
Genetic evidence predicts a causative role for amyloid-β (Aβ) in Alzheimer's disease. Recent debate has focused on whether fibrils (amyloid) or soluble oligomers of Aβ are the active species that contribute to neurodegeneration and dementia. We developed two aggregation protocols for the con...
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Published in: | The Journal of biological chemistry 2002-08, Vol.277 (35), p.32046 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | Genetic evidence predicts a causative role for amyloid-β (Aβ) in Alzheimer's disease. Recent debate has focused on whether
fibrils (amyloid) or soluble oligomers of Aβ are the active species that contribute to neurodegeneration and dementia. We
developed two aggregation protocols for the consistent production of stable oligomeric or fibrillar preparations of Aβ-(1â42).
Here we report that oligomers inhibit neuronal viability 10-fold more than fibrils and â¼40-fold more than unaggregated peptide,
with oligomeric Aβ-(1â42)-induced inhibition significant at 10 n m . Under Aβ-(1â42) oligomer- and fibril-forming conditions, Aβ-(1â40) remains predominantly as unassembled monomer and had
significantly less effect on neuronal viability than preparations of Aβ-(1â42). We applied the aggregation protocols developed
for wild type Aβ-(1â42) to Aβ-(1â42) with the Dutch (E22Q) or Arctic (E22G) mutations. Oligomeric preparations of the mutations
exhibited extensive protofibril and fibril formation, respectively, but were not consistently different from wild type Aβ-(1â42)
in terms of inhibition of neuronal viability. However, fibrillar preparations of the mutants appeared larger and induced significantly
more inhibition of neuronal viability than wild type Aβ-(1â42) fibril preparations. These data demonstrate that protocols
developed to produce oligomeric and fibrillar Aβ-(1â42) are useful in distinguishing the structural and functional differences
between Aβ-(1â42) and Aβ-(1â40) and genetic mutations of Aβ-(1â42). |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M201750200 |