DOI: 10.1073/pnas.222681699. Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways

Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways

10.1073/pnas.222681699

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Amyloid β-protein (Aβ) is linked to neuronal injury and death in Alzheimer's disease (AD). Of particular relevance for elucidating the role of Aβ in AD is new evidence that oligomeric forms of Aβ are potent neurotoxins that play a major role in neurodegeneration and the strong association of the 42-residue form of Aβ, Aβ42, with the disease. Detailed knowledge of the structure and assembly dynamics of Aβ thus is important for the development of properly targeted AD therapeutics. Recently, we have shown that Aβ oligomers can be cross-linked efficiently, and their relative abundances quantified, by using the technique of photo-induced cross-linking of unmodified proteins (PICUP). Here, PICUP, size-exclusion chromatography, dynamic light scattering, circular dichroism spectroscopy, and electron microscopy have been combined to elucidate fundamental features of the early assembly of Aβ40 and Aβ42. Carefully prepared aggregate-free Aβ40 existed as monomers, dimers, trimers, and tetramers, in rapid equilibrium. In contrast, Aβ42 preferentially formed pentamer/hexamer units (paranuclei) that assembled further to form beaded superstructures similar to early protofibrils. Addition of Ile-41 to Aβ40 was sufficient to induce formation of paranuclei, but the presence of Ala-42 was required for their further association. These data demonstrate that Aβ42 assembly involves formation of several distinct transient structures that gradually rearrange into protofibrils. The strong etiologic association of Aβ42 with AD may thus be a result of assemblies formed at the earliest stages of peptide oligomerization.

Bibliography

Bitan, G., Kirkitadze, M. D., Lomakin, A., Vollers, S. S., Benedek, G. B., & Teplow, D. B. (2002). Amyloid Î²-protein (AÎ²) assembly: AÎ²40 and AÎ²42 oligomerize through distinct pathways. Proceedings of the National Academy of Sciences, 100(1), 330â335.

Authors 6

Gal Bitan (first)
Marina D. Kirkitadze (additional)
Aleksey Lomakin (additional)
Sabrina S. Vollers (additional)
George B. Benedek (additional)
David B. Teplow (additional)

References 38 Referenced 1,116

Dates

Type	When
Created	22 years, 7 months ago (Jan. 7, 2003, 12:22 p.m.)
Deposited	3 years, 4 months ago (April 25, 2022, 9:27 p.m.)
Indexed	8 hours, 16 minutes ago (Sept. 3, 2025, 7:17 a.m.)
Issued	22 years, 8 months ago (Dec. 27, 2002)
Published	22 years, 8 months ago (Dec. 27, 2002)
Published Online	22 years, 8 months ago (Dec. 27, 2002)
Published Print	22 years, 7 months ago (Jan. 7, 2003)

Funders 0

None

BibTeX

@article{Bitan_2002, title={Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways}, volume={100}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.222681699}, DOI={10.1073/pnas.222681699}, number={1}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Bitan, Gal and Kirkitadze, Marina D. and Lomakin, Aleksey and Vollers, Sabrina S. and Benedek, George B. and Teplow, David B.}, year={2002}, month=dec, pages={330–335} }

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  "abstract": "<jats:p>Amyloid \u03b2-protein (A\u03b2) is linked to neuronal injury and death in Alzheimer's disease (AD). Of particular relevance for elucidating the role of A\u03b2 in AD is new evidence that oligomeric forms of A\u03b2 are potent neurotoxins that play a major role in neurodegeneration and the strong association of the 42-residue form of A\u03b2, A\u03b242, with the disease. Detailed knowledge of the structure and assembly dynamics of A\u03b2 thus is important for the development of properly targeted AD therapeutics. Recently, we have shown that A\u03b2 oligomers can be cross-linked efficiently, and their relative abundances quantified, by using the technique of photo-induced cross-linking of unmodified proteins (PICUP). Here, PICUP, size-exclusion chromatography, dynamic light scattering, circular dichroism spectroscopy, and electron microscopy have been combined to elucidate fundamental features of the early assembly of A\u03b240 and A\u03b242. Carefully prepared aggregate-free A\u03b240 existed as monomers, dimers, trimers, and tetramers, in rapid equilibrium. In contrast, A\u03b242 preferentially formed pentamer/hexamer units (paranuclei) that assembled further to form beaded superstructures similar to early protofibrils. Addition of Ile-41 to A\u03b240 was sufficient to induce formation of paranuclei, but the presence of Ala-42 was required for their further association. These data demonstrate that A\u03b242 assembly involves formation of several distinct transient structures that gradually rearrange into protofibrils. The strong etiologic association of A\u03b242 with AD may thus be a result of assemblies formed at the earliest stages of peptide oligomerization.</jats:p>",
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