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 language | English (US) |
|---|---|
| Pages (from-to) | 1493-1498 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 115 |
| Issue number | 7 |
| DOIs | |
| State | Published - Feb 13 2018 |
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All Science Journal Classification (ASJC) codes
- General
Keywords
- Alzheimer’s disease
- Amyloid-beta plaques
- Lysosomal enzyme tripeptidyl peptidase 1
- Mass spectrometry
- Molecular dynamics simulations
Cite this
}
Lysosomal enzyme tripeptidyl peptidase 1 destabilizes fibrillar Aβ by multiple endoproteolytic cleavages within the β-sheet domain. / Solé-Domènech, Santiago; Rojas, Ana V.; Maisuradze, Gia G.; Scheraga, Harold A.; Lobel, Peter; Maxfield, Frederick R.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 7, 13.02.2018, p. 1493-1498.Research output: Contribution to journal › Article
TY - JOUR
T1 - Lysosomal enzyme tripeptidyl peptidase 1 destabilizes fibrillar Aβ by multiple endoproteolytic cleavages within the β-sheet domain
AU - Solé-Domènech, Santiago
AU - Rojas, Ana V.
AU - Maisuradze, Gia G.
AU - Scheraga, Harold A.
AU - Lobel, Peter
AU - Maxfield, Frederick R.
PY - 2018/2/13
Y1 - 2018/2/13
N2 - 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.
AB - 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.
KW - Alzheimer’s disease
KW - Amyloid-beta plaques
KW - Lysosomal enzyme tripeptidyl peptidase 1
KW - Mass spectrometry
KW - Molecular dynamics simulations
UR - http://www.scopus.com/inward/record.url?scp=85041944529&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041944529&partnerID=8YFLogxK
U2 - 10.1073/pnas.1719808115
DO - 10.1073/pnas.1719808115
M3 - Article
C2 - 29378960
AN - SCOPUS:85041944529
VL - 115
SP - 1493
EP - 1498
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 7
ER -