Abstract
A key hallmark of Alzheimer’s disease is the extracellular deposition of amyloid plaques composed primarily of the amyloidogenic amyloid-β (Aβ) peptide. The Aβ peptide is a product of sequential cleavage of the Amyloid Precursor Protein, the first step of which gives rise to a C-terminal Fragment (C99). Cleavage of C99 by γ-secretase activity releases Aβ of several lengths and the Aβ42 isoform in particular has been identified as being neurotoxic. The misfolding of Aβ 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 Aβ42 and show its assembly enhancing properties which are dependent on the Aβ 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.
Highlights
A key hallmark of Alzheimer’s disease is the extracellular deposition of amyloid plaques composed primarily of the amyloidogenic amyloid-β (Aβ) peptide
In line with what has previously been shown by our group, we confirm that cells transfected with consisting of 99 amino acids (C99) produce a detectable band corresponding to an Aβ assembly size of ~ 28 kDa; the theoretical size of an Aβ42 h examer[43]
We assessed the Aβ profile of cells transfected with the Aβ40 and Aβ42 sequences affixed with the Amyloid Precursor Protein (APP) signal peptide, to understand whether the formation of this hexamer in a cellular context was related to one or both of these Aβ isoforms (Fig. 1b)
Summary
A key hallmark of Alzheimer’s disease is the extracellular deposition of amyloid plaques composed primarily of the amyloidogenic amyloid-β (Aβ) peptide. There is first the nucleation or lag phase where the monomer precursor is either in an unfolded, partially folded or natively folded state and undergoes usually unfavourable self-association to form nuclei that are critical for further self-assembly[20]. This critical nucleus is defined as the smallest assembly size that grows faster by the addition of monomers, than dissociates back to smaller assemblies including monomers[21]. Once the critical nucleus has been formed, there is a rapid formation of fibrils by the addition of monomers This is the elongation phase and fibril formation in this way is known as primary nucleation. It has been shown that the formation of hexameric Aβ42 is an early event in the self-assembly pathway[23,24,27,28] and the identification of several multimers of hexamers e.g. Aβ derived diffusible ligands (ADDLs), Aβ*56 and globulomers, provide a Scientific Reports | (2021) 11:11570
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