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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.