A beta dimers differ from monomers in structural propensity, aggregation paths and population of synaptotoxic assemblies

作者：O' Malley Tiernan T; Oktaviani Nur Alia; Zhang Dainan; Lomakin Aleksey; O' Nuallain Brian; Linse Sara; Benedek George B; Rowan Michael J; Mulder Frans A A^*; Walsh Dominic M

来源：Biochemical Journal, 2014, 461(3): 413-426.

DOI：10.1042/BJ20140219

• Alzheimer%26apos
• s disease
• amyloid beta-protein
• long-term potentiation
• nuclear magnetic resonance (NMR)
• synaptic plasticity

Dimers of A beta (amyloid beta-protein) are believed to play an important role in Alzheimer%26apos;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%26apos;s disease results from the ability of dimers to further assemble and form synaptotoxic assemblies that persist for long periods of time.

• 出版日期2014-8-1