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Amyloid β-Protein Dimers Rapidly Form Stable Synaptotoxic Protofibrils
O'Nuallain, Brian; Freir, Darragh; Nicoll, Andrew J.; Ferguson, Neil; Herron, Caroline; Walsh, Dominic; et al.
Nonfibrillar, water-soluble low-molecular weight assemblies of the amyloid beta-protein (A beta) are believed to play an important role in Alzheimer's disease (AD). Aqueous extracts of human brain contain A beta assemblies that migrate on SDS-polyacrylamide gels and elute from size exclusion as dimers (similar to 8 kDa) and can block long-term potentiation and impair memory consolidation in the rat. Such species are detected specifically and sensitively in extracts of Alzheimer brain suggesting that SDS-stable dimers may be the basic building blocks of AD-associated synaptotoxic assemblies. Consequently, understanding the structure and properties of A beta dimers is of great interest. In the absence of sufficient brain-derived dimer to facilitate biophysical analysis, we generated synthetic dimers designed to mimic the natural species. For this, A beta(1-40) containing cysteine in place of serine 26 was used to produce disulphide cross-linked dimer, (A beta S26C)(2). Such dimers had no detectable secondary structure, produced an analytical ultracentrifugation profile consistent for an similar to 8.6 kDa protein, and had no effect on hippocampal long-term potentiation (LTP). However, (A beta S26C)(2) aggregated more rapidly than either A beta S26C or wild-type monomers and formed parastable beta-sheet rich, thioflavin T-positive, protofibril-like assemblies. Whereas wildtype A beta aggregated to form typical amyloid fibrils, the protofibril-like structures formed by (A beta S26C)(2) persisted for prolonged periods and potently inhibited LIP in mouse hippocampus. These data support the idea that A beta dimers may stabilize the formation of fibril intermediates by a process distinct from that available to A beta monomer and that higher molecular weight prefibrillar assemblies are the proximate mediators of A beta toxicity. Health Research Board Science Foundation Ireland National Institutes of Health
Keyword(s): Long-term potentiation; Alzheimers-disease; A-beta; Synaptic plasticity; In-vitro; Peptide; Fibrillogenesis; Aggregation; Oligomers; Correlate
Publication Date:
Type: Journal article
Peer-Reviewed: Unknown
Language(s): English
Institution: University College Dublin
Publisher(s): Society for Neuroscience
Alternative Title(s): Amyloid beta-Protein Dimers Rapidly Form Stable Synaptotoxic Protofibrils -Aβ Dimers Rapidly Form Stable Synaptotoxic Protofibrils
First Indexed: 2015-08-09 05:29:05 Last Updated: 2018-10-11 15:32:14