Pulsed Hydrogen-Deuterium Exchange Reveals Altered Structures and Mechanisms in the Aggregation of Familial Alzheimer's Disease Mutants.

ABSTRACT: Mutations of the Amyloid Precursor Protein, from which the amyloid β peptide Aβ42 is cleaved, are associated with familial Alzheimer's disease. The disease-relevant familial mutations include the Arctic (E22G), Iowa (D23N), Italian (E22K), Dutch (E22Q), Japanese (D7N), English (D6R), and Flemish (A21G) variants. A detailed mechanistic understanding of the aggregation behavior of the mutant peptides at the residue level is, however, still lacking. We report here a study of the aggregation kinetics of these mutants in vitro by pulsed hydrogen-deuterium exchange mass spectrometry (HDX-MS) to obtain a temporally and sequence resolved picture of their self-assembly. For all variants, HDX occurs to give a bimodal distribution representing two soluble classes of aggregates, one protected and one

SUBMITTER: Illes-Toth E 

PROVIDER: S-EPMC8894311 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature