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Updated: Sep 25, 2025

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Mucin-Type O-Glycosylation Proximal to β-Secretase Cleavage Site Affects APP Processing and Aggregation Fate

YashoNandini Singh1, Deepika Regmi1, David Ormaza1

  • 1Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, FL, United States.

Frontiers in Chemistry
|April 25, 2022
PubMed

Insights

O-glycosylation and the Swedish mutation on amyloid-β precursor protein (APP) increase its susceptibility to beta-secretase cleavage, impacting amyloid-beta aggregation kinetics in Alzheimer's disease (AD) research.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Glycobiology

Background:

  • Amyloid-β precursor protein (APP) processing by secretases generates amyloid-β (Aβ) peptides, central to Alzheimer's disease (AD) pathology.
  • O-glycosylation of APP is increasingly recognized for its potential role in modulating APP processing and AD-related mechanisms.
  • Previous work indicated Tyr681 O-glycosylation and the Swedish mutation accelerate APP cleavage via the amyloidogenic pathway.

Purpose of the Study:

  • To investigate the impact of O-glycosylation at Thr663 and/or Ser667 on APP conformation, secretase activity, and Aβ40 aggregation kinetics.
  • To compare the effects of native and Swedish-mutated APP glycopeptides.
  • To elucidate the role of O-glycosylation and glycan density in APP processing and Aβ aggregation.

Main Methods:

  • Synthesis of native and Swedish-mutated APP model glycopeptides with O-GalNAc modifications.
  • Analysis of glycopeptide conformation under varying buffer and solvent conditions.
  • Assays to measure β-secretase activity and Aβ40 aggregation kinetics.

Main Results:

  • Glycopeptide conformation is influenced by external conditions and internal modifications, including O-glycosylation and the Swedish mutation.
  • β-secretase activity is significantly elevated in Swedish-mutated glycopeptides compared to non-glycosylated and native counterparts.
  • Glycopeptides delay Aβ40 aggregation onset by increasing the lag phase, with a less pronounced effect for Swedish-mutated variants.

Conclusions:

  • O-glycosylation and the Swedish mutation enhance APP susceptibility to β-secretase cleavage.
  • These modifications influence the aggregation kinetics of Aβ40.
  • Findings highlight the potential role of glycosylation and glycan density in modulating APP processing and AD pathogenesis.
Keywords:
APP O-glycopeptidesAlzheimer’s diseaseaggregation kineticscircular dichroismproteolysis

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