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Updated: Oct 11, 2025

Rapid Generation of Amyloid from Native Proteins In vitro
05:48

Rapid Generation of Amyloid from Native Proteins In vitro

Published on: December 5, 2013

6.3K

Proteolysis of Amyloid β by Lysosomal Enzymes as a Function of Fibril Morphology

Tyler R Lambeth1, Ryan R Julian1

  • 1Department of Chemistry, University of California, Riverside, California 92521, United States.

ACS Omega
|December 6, 2021
PubMed

Insights

Alzheimer's disease amyloid-beta (Aβ) fibrils resist digestion by lysosomal enzymes. Fibrils formed at neutral pH, especially Aβ 1-42, are most resistant, hindering clearance.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Cell Biology

Background:

  • Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) plaques and impaired lysosomal function within dystrophic neurites.
  • Lysosomal proteolysis is crucial for clearing cellular waste, including protein aggregates.
  • The interaction between Aβ fibril formation and lysosomal enzyme activity remains incompletely understood.

Purpose of the Study:

  • To investigate whether amyloid-beta (Aβ) fibril formation impedes proteolysis by lysosomal cathepsins.
  • To compare the resistance of Aβ 1-40 and Aβ 1-42 fibrils, formed at neutral and acidic pH, to cathepsin digestion.

Main Methods:

  • Amyloid-beta (Aβ) 1-40 and Aβ 1-42 fibrils were prepared under neutral and acidic pH conditions.
  • Proteolysis by cathepsins (L, D, B, H) was assessed using thioflavin T fluorescence and liquid chromatography-mass spectrometry.
  • Resistance to digestion was evaluated across the entire Aβ sequence.

Main Results:

  • All tested Aβ fibril morphologies demonstrated resistance to cathepsin digestion under both neutral and acidic conditions.
  • Fibrils grown at neutral pH exhibited resistance throughout the sequence, while acid-grown fibrils were primarily resistant at the C-terminus.
  • Amyloid-beta (Aβ) 1-42 fibrils were generally more resistant to degradation than Aβ 1-40 fibrils.

Conclusions:

  • Amyloid-beta (Aβ) fibrils are resistant to lysosomal enzyme digestion, suggesting a mechanism for their accumulation in Alzheimer's disease (AD).
  • Aβ fibrils formed in neutral pH environments, particularly those composed of Aβ 1-42, present the most significant challenge for lysosomal clearance.
  • These findings highlight the potential role of impaired Aβ degradation in AD pathogenesis.

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