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Xiao Y, Ma B, McElheny D, Parthasarathy S, Long F, Hoshi M, Nussinov R, Ishii Y. Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease. Nat Struct Mol Biol. 2015 Jun;22(6):499-505. Epub 2015 May 4 PubMed.
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University of California, Irvine
This is an interesting paper that underscores the conformational polymorphisms in β-sheet aggregates of Aβ. This one is unique in two aspects: It is the first structure that is a triple parallel, in-register sheet, and it is unique to Aβ42. I’m not sure how many unique structures there are so far, but at least four distinct, parallel, in-register structures. There is also evidence for antiparallel β-sheet oligomers, but the structural details of these are not as well-known as the parallel β-sheets.
The triple-sheet 42 structure does not appear to seed 40 fibrillization, so there appears to be at least two structures that Aβ42 can adopt: the unique triple-sheet structure that does not seed Aβ40 and a structure that can seed Aβ40 fibrillization that may be a two-sheet β hairpin (Jarrett et al., 1993). The unique structure of Aβ42 is consistent with results obtained with several conformation-dependent monoclonal antibodies that appear to be specific for Aβ42 fibrils and do not recognize Aβ40 fibrils, but yet recognize amino terminal and central epitopes rather than the carboxyl terminus (Hatami et al., 2014). The challenge for the future will be understanding which structures are more closely related to pathology and whether they are pathogenic by the same mechanism.
References:
Jarrett JT, Berger EP, Lansbury PT. The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry. 1993 May 11;32(18):4693-7. PubMed.
Hatami A, Albay R 3rd, Monjazeb S, Milton S, Glabe C. Monoclonal antibodies against Aβ42 fibrils distinguish multiple aggregation state polymorphisms in vitro and in Alzheimer disease brain. J Biol Chem. 2014 Nov 14;289(46):32131-43. Epub 2014 Oct 3 PubMed.
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