Lysosomal enzyme tripeptidyl peptidase 1 destabilizes fibrillar A? by multiple endoproteolytic cleavages within the ?-sheet domain.

ABSTRACT: Accumulation of amyloid-beta (A?), which is associated with Alzheimer's disease, can be caused by excess production or insufficient clearance. Because of its ?-sheet structure, fibrillar A? is resistant to proteolysis, which would contribute to slow degradation of A? plaques in vivo. Fibrillar A? 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 A?. 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 A? efficiently. Mass spectrometry analysis of peptides released from fibrillar A? digested with TPP1 reveals several endoproteolytic cleavages including some within ?-sheet regions that are important for fibril formation. Using molecular dynamics simulations, we demonstrate that these cleavages destabilize fibrillar ?-sheet structure. The demonstration that TPP1 can degrade fibrillar forms of A? provides insight into the turnover of fibrillar A? and may lead to new therapeutic methods to increase degradation of A? plaques.

SUBMITTER: Sole-Domenech S 

PROVIDER: S-EPMC5816203 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature