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bioRxiv · 10.1101/2020.12.15.422916

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.
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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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Vadukul, D. M., Vrancx, C., Burguet, P., Contino, S., Suelves, N., Serpell, L. C., Quinton, L., Kienlen-Campard, P.. 2020-12-15. Cell-derived hexameric β-amyloid: a novel insight into composition, self-assembly and nucleating properties. https://doi.org/10.1101/2020.12.15.422916

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