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Updated: Feb 26, 2026

Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain
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Probing APP Cleavage and Amyloid-β Assembly via Synthetic MUC-Type O-Glycosylated APP Glycopeptides

Nancy Vela Navarro1, Gustavo De Nadai Mundim1, Deepika Regmi1

  • 1Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, Florida 33431, United States.

ACS Chemical Neuroscience
|February 25, 2026
PubMed

Insights

Aberrant O-glycosylation of amyloid precursor protein (APP) influences its processing and aggregation. Site-specific glycosylation and mutations alter amyloid-beta (Aβ) peptide pathways, impacting Alzheimer's disease pathogenesis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Neuroscience

Background:

  • Aberrant proteolytic processing of amyloid precursor protein (APP) is linked to amyloid-beta (Aβ) peptide trafficking.
  • MUC1-type O-glycosylation is implicated as a factor modulating APP processing.

Purpose of the Study:

  • To investigate the impact of site-specific O-glycosylation and the Swedish mutation on APP structure, processing, and aggregation.
  • To elucidate how glycosylation at Thr663, Ser667, and/or Tyr681 affects APP's secondary structure and secretase cleavage.

Main Methods:

  • Synthesis of native and Swedish-mutated APP glycopeptides with O-GalNAc moieties.
  • Circular dichroism (CD) for conformational analysis.
  • Analysis of secretase (BACE1 and ADAM10) cleavage.
  • In vitro assays (coincubation with Aβ40, ThT kinetics, AFM/TEM imaging, DLS) to study fibril formation and oligomerization.

Main Results:

  • Glycosylation site and density influenced APP conformation, with increased valency favoring β-turn-rich structures.
  • The Swedish mutation enhanced BACE1 cleavage, particularly with Ser667 glycosylation.
  • Additional glycans shifted processing towards ADAM10, but did not fully counteract amyloidogenesis.
  • Ser667 glycosylation promoted Aβ40 fibril formation, while di- and triglycosylation disrupted fibrils and favored oligomers.

Conclusions:

  • Site-specific glycosylation and mutations critically shape APP proteolytic processing and secondary structure.
  • Glycosylation patterns influence APP aggregation behavior, affecting fibril architecture and oligomer formation.
  • These findings are crucial for understanding APP function in health and disease, particularly Alzheimer's disease.
Keywords:
AFM and TEMAlzheimer’s diseaseMUC-type glycosylationaggregationproteolytic cleavage

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