Journal of Biological Chemistry
Volume 277, Issue 35, 30 August 2002, Pages 32046-32053
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PROTEIN STRUCTURE AND FOLDING
Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability*

https://doi.org/10.1074/jbc.M201750200Get rights and content
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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-(1–42). Here we report that oligomers inhibit neuronal viability 10-fold more than fibrils and ∼40-fold more than unaggregated peptide, with oligomeric Aβ-(1–42)-induced inhibition significant at 10 nm. Under Aβ-(1–42) oligomer- and fibril-forming conditions, Aβ-(1–40) remains predominantly as unassembled monomer and had significantly less effect on neuronal viability than preparations of Aβ-(1–42). We applied the aggregation protocols developed for wild type Aβ-(1–42) to Aβ-(1–42) 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-(1–42) 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-(1–42) fibril preparations. These data demonstrate that protocols developed to produce oligomeric and fibrillar Aβ-(1–42) are useful in distinguishing the structural and functional differences between Aβ-(1–42) and Aβ-(1–40) and genetic mutations of Aβ-(1–42).

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Published, JBC Papers in Press, June 10, 2002, DOI 10.1074/jbc.M201750200

*

This research was supported by National Institutes of Health Grants AG19121 (to M. J. L. D.), AG13496 (to G. K.), and AG15501 (to G.K.) and Alzheimer's Association Grant IIRG-01-3073 (to M. J. L. D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Acumen Pharmaceuticals, Inc., Glenview, IL 60025.