Display Settings:

Format

Send to:

Choose Destination
J Biol Chem. 2014 Jan 17;289(3):1540-50. doi: 10.1074/jbc.M113.498246. Epub 2013 Nov 13.

Characterization of intermediate steps in amyloid beta (Aβ) production under near-native conditions.

Author information

  • 1From the AstraZeneca iMED CNS/Pain, 15185 Södertälje, Sweden.

Abstract

Processing of the amyloid precursor protein (APP) by γ-secretase results in generation of Aβ peptides of different lengths ranging from 51 to 30 residues. Accumulation of Aβ and in particular Aβ42 is enhanced by familial Alzheimer disease (FAD) causing mutations in APP and is believed to play a pivotal role. The molecular mechanism underlying normal Aβ production, the impact of FAD mutations on this process and how anti-amyloidogenic γ-secretase modulators (GSMs) cause a selective decrease in Aβ40 and Aβ42 and an increase in shorter Aβ peptides, however, is poorly understood. By using a combined immuno- and LC-MS-based assay we identify several major intermediates, i.e. 3- and 4-peptides that line up head to head across the entire APP transmembrane sequence from Aβ51 to Aβ31/Aβ30 and from Aβ49 to Aβ30/31. FAD APP mutations displayed a relative increase in 3- and 4-peptides from Aβ48 to Aβ38 compared with Aβ49 to Aβ37. These findings correlate with an increase in the Aβ42/40 ratio. GSMs caused a decrease in Aβ40 and Aβ42 and an increase in Aβ37 and Aβ38 paralleled by an increase of the intermediates Aβ40-38 and Aβ42-39. Collectively, these data provide a thorough characterization of all intermediate steps in Aβ production in native cell membranes and provide key mechanistic insights to genetic and pharmacological modulation of Aβ generation.

KEYWORDS:

Alzheimer Disease; Amyloid; Amyloid Precursor Protein; Intramembrane Proteolysis; Secretases

PMID:
24225948
[PubMed - indexed for MEDLINE]
PMCID:
PMC3894335
[Available on 2015/1/17]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire
    Loading ...
    Write to the Help Desk