Sole-Domenech_2018_Proc.Natl.Acad.Sci.U.S.A_115_1493

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