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Biochem J. 2014 Aug 1;461(3):413-26. doi: 10.1042/BJ20140219.

Aβ dimers differ from monomers in structural propensity, aggregation paths and population of synaptotoxic assemblies.

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‡Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9749 AB Groningen, The Netherlands.
§Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland.
∥Department of Physics and Materials Processing Center, Massachusetts Institute of Technology, Cambridge, MA 02139, U.S.A.
*Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, U.S.A.
¶Department of Biophysical Chemistry, Lund University, SE221 00 Lund, Sweden.


Dimers of Aβ (amyloid β-protein) are believed to play an important role in Alzheimer's disease. In the absence of sufficient brain-derived dimers, we studied one of the only possible dimers that could be produced in vivo, [Aβ](DiY) (dityrosine cross-linked Aβ). For comparison, we used the Aβ monomer and a design dimer cross-linked by replacement of Ser²⁶ with cystine [AβS26C]₂. We showed that similar to monomers, unaggregated dimers lack appreciable structure and fail to alter long-term potentiation. Importantly, dimers exhibit subtly different structural propensities from monomers and each other, and can self-associate to form larger assemblies. Although [Aβ](DiY) and [AβS26C]₂ have distinct aggregation pathways, they both populate bioactive soluble assemblies for longer durations than Aβ monomers. Our results indicate that the link between Aβ dimers and Alzheimer's disease results from the ability of dimers to further assemble and form synaptotoxic assemblies that persist for long periods of time.

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