Aggregation and catabolism of disease-associated intra-Aβ mutations: reduced proteolysis of AβA21G by neprilysin

Vicki Betts, Malcolm A. Leissring, Georgia Dolios, Rong Wang, Dennis J. Selkoe, Dominic M. Walsh

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

Five point mutations within the amyloid β-protein (Aβ) sequence of the APP gene are associated with hereditary diseases which are similar or identical to Alzheimer's disease and encode: the A21G (Flemish), E22G (Arctic), E22K (Italian), E22Q (Dutch) and the D23N (Iowa) amino acid substitutions. Although a substantial body of data exists on the effects of these mutations on Aβ production, whether or not intra-Aβ mutations alter degradation and how this relates to their aggregation state remain unclear. Here we report that the E22G, E22Q and the D23N substitutions significantly increase fibril nucleation and extension, whereas the E22K substitution exhibits only an increased rate of extension and the A21G substitution actually causes a decrease in the extension rate. These substantial differences in aggregation together with our observation that aggregated wild type Aβ(1-40) was much less well degraded than monomeric wild type Aβ(1-40), prompted us to assess whether or not disease-associated intra-Aβ mutations alter proteolysis independent of their effects on aggregation. Neprilysin (NEP), insulin degrading enzyme (IDE) and plasmin play a major role in Aβ catabolism, therefore we compared the ability of these enzymes to degrade wild type and mutant monomeric Aβ peptides. Experiments investigating proteolysis revealed that all monomeric peptides are degraded similarly by IDE and plasmin, but that the Flemish peptide was degraded significantly more slowly by NEP than wild type Aβ or any of the other mutant peptides. This finding suggests that resistance to NEP-mediated proteolysis may underlie the pathogenicity associated with the A21G mutation.

Original languageEnglish (US)
Pages (from-to)442-450
Number of pages9
JournalNeurobiology of Disease
Volume31
Issue number3
DOIs
StatePublished - Sep 2008

Keywords

  • Aggregation
  • Alzheimer's disease
  • Amyloid beta-protein
  • Degradation
  • Insulin degrading enzyme
  • Plasmin

ASJC Scopus subject areas

  • Neurology

Fingerprint Dive into the research topics of 'Aggregation and catabolism of disease-associated intra-Aβ mutations: reduced proteolysis of AβA21G by neprilysin'. Together they form a unique fingerprint.

Cite this