Amyloid plaque in the human brain can decompose from Aβ(1-40/1-42) by spontaneous nonenzymatic processes

RIS ID

105916

Publication Details

Lyons, B., Friedrich, M., Mark Raftery, M. & Truscott, R. (2016). Amyloid plaque in the human brain can decompose from Aβ(1-40/1-42) by spontaneous nonenzymatic processes. Analytical Chemistry, 88 (5), 2675-2684.

Abstract

The degradation of long-lived proteins in the body is an important aspect of aging, and much of the breakdown is due to the intrinsic instability of particular amino acids. In this study, peptides were examined to discover if spontaneous nonenzymatic reactions could be responsible for the composition of Alzheimer's (AD) plaque in the human brain. The great majority of AD plaque consists of N-terminally truncated versions of Aβ(1-40/1-42), with the most abundant peptide commencing with Glu (residue 3 in Aβ1-40/1-42) that is present as pyroGlu. Several Asp residues are racemized in Aβ plaque, with residue 1 being predominantly l-isoAsp and peptide bond cleavage next to Ser 8 is also evident. In peptides, loss of the two N-terminal amino acids as a diketopiperazine was demonstrated at pH 7. For the Aβ N-terminal hexapeptide, AspAlaGluPheArgHis, this resulted in the removal of AspAla diketopiperazine and the generation of Glu as the new N-terminal residue. The Glu cyclized readily to pyroGlu. This pathway was altered significantly by zinc, which promoted pyroGlu formation but decreased AspAla diketopiperazine release. Zinc also facilitated cleavage on the N-terminal side of Ser 8. Racemization of the original N-terminal Asp to l-isoAsp was also detected and loss of one amino acid from the N-terminus. These data are therefore entirely consistent with plaque in the human brain forming from deposition of Aβ(1-40/1-42) and, over time, decomposing spontaneously. Since amyloid plaque is present in the human brain for years prior to the onset of AD, gradual spontaneous changes to the polypeptides within it will alter its properties and those of the oligomers that can diffuse from it. Such incremental changes in composition may therefore contribute to the origin of AD-associated cytotoxicity.

Grant Number

NHMRC/1008667

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