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

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.

authors

Solé-Domènech S,Rojas AV,Maisuradze GG,Scheraga HA,Lobel P,Maxfield FR

doi

10.1073/pnas.1719808115

subject

Has Abstract

pub_date

2018-02-13 00:00:00

pages

1493-1498

issue

7

eissn

0027-8424

issn

1091-6490

pii

1719808115

journal_volume

115

pub_type

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