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Cell-derived hexameric β-amyloid: a novel insight into composition, self-assembly and nucleating properties

Vadukul, D. M.; Vrancx, C.; Burguet, P.; Contino, S.; Suelves, N.; Serpell, L. C.; Quinton, L.; Kienlen-Campard, P.

2020-12-15 biochemistry
10.1101/2020.12.15.422916 bioRxiv
Show abstract

A key hallmark of Alzheimers disease (AD) is the extracellular deposition of amyloid plaques composed primarily of the amyloidogenic amyloid-{beta} (A{beta}) peptide. The A{beta} peptide is a product of sequential cleavage of the Amyloid Precursor Protein (APP), the first step of which gives rise to a C-terminal Fragment (C99). Cleavage of C99 by {gamma}-secretase activity releases A{beta} of several lengths and the A{beta}42 isoform in particular has been identified as being neurotoxic. The misfolding of A{beta} leads to subsequent amyloid fibril formation by nucleated polymerisation. This requires an initial and critical nucleus for self-assembly. Here, we identify and characterise the composition and self-assembly properties of cell-derived hexameric A{beta}42 and show its nucleating properties which are dependent on the A{beta} monomer availability. Identification of nucleating assemblies that contribute to self-assembly in this way may serve as therapeutic targets to prevent the formation of toxic oligomers.

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