ArticleProceedings of the National Academy of Sciences of the United States of America2018
Lysosomal enzyme tripeptidyl peptidase 1 destabilizes fibrillar Aβ by multiple endoproteolytic cleavages within the β-sheet domain.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 46 citations in OpenAlex.
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- Protocol for the quantification of digestive exophagy in cell culture.STAR protocols · 2026Article
- Systematic discovery of disease-modifying targets by prediction from knowledge graph-based AI model and experimental validation: Parkinson's disease case.Computational and structural biotechnology journal · 2026Article
- Neuronal ceroid lipofuscinosis: underlying mechanisms and emerging therapeutic targets.Nature reviews. Neurology · 2025Review
- Real-time pH imaging of macrophage lysosomes using the pH-sensitive probe ApHID.Cell reports methods · 2025Article
- GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice.JCI insight · 2025Article
- Microglial Clearance of Alzheimer's Amyloid-Beta Obstructed by Nanoplastics.Environmental science. Nano · 2025Article
- Survival strategies of Rhinocladiella similis in perchlorate-rich Mars like environments.NPJ microgravity · 2025Article
- Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer's disease, and late-onset Alzheimer's disease.Acta neuropathologica · 2025Article
- Microglia degrade Alzheimer's amyloid-beta deposits extracellularly via digestive exophagy.Cell reports · 2024Article
- Microglia and Astrocytes in Alzheimer's Disease: Significance and Summary of Recent Advances.Aging and disease · 2024Review
- Comparison of the Amyloid Plaque Proteome in Down Syndrome, Early-Onset Alzheimer's Disease and Late-Onset Alzheimer's Disease.Research square · 2024Article
- Deciphering the Role of Rapidly Evolving Conserved Elements in Primate Brain Development and Exploring Their Potential Involvement in Alzheimer's Disease.Molecular biology and evolution · 2024Article
- Converging links between adult-onset neurodegenerative Alzheimer's disease and early life neurodegenerative neuronal ceroid lipofuscinosis?Neural regeneration research · 2023Review
- AP2S1 regulates APP degradation through late endosome-lysosome fusion in cells and APP/PS1 mice.Traffic (Copenhagen, Denmark) · 2023Article
- Elevated levels of tripeptidyl peptidase 1 do not ameliorate pathogenesis in a mouse model of Alzheimer disease.Neurobiology of aging · 2022Article
- The amyloid plaque proteome in early onset Alzheimer's disease and Down syndrome.Acta neuropathologica communications · 2022Article
- A multifaceted role of progranulin in regulating amyloid-beta dynamics and responses.Life science alliance · 2021Article
- Psychological Stress as a Risk Factor for Accelerated Cellular Aging and Cognitive Decline: The Involvement of Microglia-Neuron Crosstalk.Frontiers in molecular neuroscience · 2021Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.