On the role of sidechain size and charge in the aggregation of Aβ42 with familial mutations

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

The aggregation of the amyloid-β (Aβ) peptide is linked to the pathogenesis of Alzheimer’s disease (AD). In particular, some point mutations within Aβ are associated with early-onset familial Alzheimer’s disease. Here we set out to explore how the physical properties of the altered side chains, including their sizes and charges, affect the molecular mechanisms of aggregation. We focus on Aβ42 with familial mutations—A21G (Flemish), E22K (Italian), E22G (Arctic), E22Q (Dutch), and D23N (Iowa)—which lead to similar or identical pathology with sporadic AD or severe cerebral amyloid angiopathy. Through global kinetic analysis, we find that for the E22K, E22G, E22Q, and D23N mutations, the acceleration of the overall aggregation originates primarily from the modulation of the nucleation processes, in particular secondary nucleation on the surface of existing fibrils, whereas the elongation process is not significantly affected. Remarkably, the D23 position appears to be responsible for most of the charge effects during nucleation, while the size of the side chain at the E22 position plays a more significant role than its charge. Thus, we have developed a kinetic approach to determine the nature and the magnitude of the contribution of specific residues to the rate of individual steps of the aggregation reaction, through targeted mutations and variations in ionic strength. This strategy can help rationalize the effect of some disease-related mutations as well as yield insights into the mechanism of aggregation and the transition states of the wild-type protein.

Detaljer

Författare
  • Xiaoting Yang
  • Georg Meisl
  • Birgitta Frohm
  • Eva Thulin
  • Tuomas P.J. Knowles
  • Sara Linse
Enheter & grupper
Externa organisationer
  • University of Cambridge
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Läkemedelskemi
  • Cell- och molekylärbiologi

Nyckelord

Originalspråkengelska
Sidor (från-till)E5849-E5858
TidskriftProceedings of the National Academy of Sciences of the United States of America
Volym115
Utgivningsnummer26
StatusPublished - 2018 jun 26
PublikationskategoriForskning
Peer review utfördJa