Journal
BIOCHEMICAL JOURNAL
Volume 461, Issue -, Pages 413-426Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20140219
Keywords
Alzheimer's disease; amyloid beta-protein; long-term potentiation; nuclear magnetic resonance (NMR); synaptic plasticity
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Funding
- Foundation for Neurologic Diseases
- Netherlands Organization for Scientific Research [VIDI 700.56.422]
- Swedish Research Council [521-2013-3679]
- Science Foundation Ireland [10/IN.I/B3001]
- Health Research Board of Ireland [COEN/2011/11]
- Health Research Board (HRB) [COEN-2011-11] Funding Source: Health Research Board (HRB)
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Dimers of A beta (amyloid beta-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, [A beta](DiY) (dityrosine cross-linked A beta). For comparison, we used the A beta monomer and a design dimer cross-linked by replacement of Ser(26) with cystine [A beta S26C](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 [A beta](DiY) and [A beta S26C](2) have distinct aggregation pathways, they both populate bioactive soluble assemblies for longer durations than A beta monomers. Our results indicate that the link between A beta 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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