Lysosomal enzyme tripeptidyl peptidase 1 destabilizes fibrillar Aβ by multiple endoproteolytic cleavages within the β-sheet domain

Santiago Solé-Domènech, Ana V. Rojas, Gia G. Maisuradze, Harold A. Scheraga, Peter Lobel, Frederick R. Maxfield

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Accumulation of amyloid-beta (Aβ), which is associated with Alzheimer’s disease, can be caused by excess production or insufficient clearance. Because of its β-sheet structure, fibrillar Aβ is resistant to proteolysis, which would contribute to slow degradation of Aβ plaques in vivo. Fibrillar Aβ can be internalized by microglia, which are the scavenger cells of the brain, but the fibrils are degraded only slowly in microglial lysosomes. Cathepsin B is a lysosomal protease that has been shown to proteolyze fibrillar Aβ. Tripeptidyl peptidase 1 (TPP1), a lysosomal serine protease, possesses endopeptidase activity and has been shown to cleave peptides between hydrophobic residues. Herein, we demonstrate that TPP1 is able to proteolyze fibrillar Aβ efficiently. Mass spectrometry analysis of peptides released from fibrillar Aβ digested with TPP1 reveals several endoproteolytic cleavages including some within β-sheet regions that are important for fibril formation. Using molecular dynamics simulations, we demonstrate that these cleavages destabilize fibrillar β-sheet structure. The demonstration that TPP1 can degrade fibrillar forms of Aβ provides insight into the turnover of fibrillar Aβ and may lead to new therapeutic methods to increase degradation of Aβ plaques.

Original languageEnglish (US)
Pages (from-to)1493-1498
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number7
DOIs
StatePublished - Feb 13 2018

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Alzheimer’s disease
  • Amyloid-beta plaques
  • Lysosomal enzyme tripeptidyl peptidase 1
  • Mass spectrometry
  • Molecular dynamics simulations

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