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

Content Provider	PubMed Central
Author	Gal, Bitan Kirkitadze, Marina D. Lomakin, Aleksey Vollers, Sabrina S. Benedek, George B. Teplow, David B.
Copyright Year	2003
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.
Related Links	http://dx.doi.org/10.1073/pnas.222681699
Ending Page	335
Page Count	6
Starting Page	330
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	1
Volume Number	100
Language	English
Publisher	The National Academy of Sciences
Publisher Date	2003-01-07
Access Restriction	Open
Rights Holder	The National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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