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The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-β production
Abstract
Neuropathological hallmarks of Alzheimer's disease are neurofibrillary tangles composed of tau and neuritic plaques comprising amyloid-beta peptides (Abeta) derived from amyloid precursor protein (APP), but their exact relationship remains elusive. Phosphorylation of tau and APP on certain serine or threonine residues preceding proline affects tangle formation and Abeta production in vitro. Phosphorylated Ser/Thr-Pro motifs in peptides can exist in cis or trans conformations, the conversion of which is catalysed by the Pin1 prolyl isomerase. Pin1 has been proposed to regulate protein function by accelerating conformational changes, but such activity has never been visualized and the biological and pathological significance of Pin1 substrate conformations is unknown. Notably, Pin1 is downregulated and/or inhibited by oxidation in Alzheimer's disease neurons, Pin1 knockout causes tauopathy and neurodegeneration, and Pin1 promoter polymorphisms appear to associate with reduced Pin1 levels and increased risk for late-onset Alzheimer's disease. However, the role of Pin1 in APP processing and Abeta production is unknown. Here we show that Pin1 has profound effects on APP processing and Abeta production. We find that Pin1 binds to the phosphorylated Thr 668-Pro motif in APP and accelerates its isomerization by over 1,000-fold, regulating the APP intracellular domain between two conformations, as visualized by NMR. Whereas Pin1 overexpression reduces Abeta secretion from cell cultures, knockout of Pin1 increases its secretion. Pin1 knockout alone or in combination with overexpression of mutant APP in mice increases amyloidogenic APP processing and selectively elevates insoluble Abeta42 (a major toxic species) in brains in an age-dependent manner, with Abeta42 being prominently localized to multivesicular bodies of neurons, as shown in Alzheimer's disease before plaque pathology. Thus, Pin1-catalysed prolyl isomerization is a novel mechanism to regulate APP processing and Abeta production, and its deregulation may link both tangle and plaque pathologies. These findings provide new insight into the pathogenesis and treatment of Alzheimer's disease.
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“Endosomal Aβ42 labeling by immuno-EM has since been confirmed by other groups [49, 95, 143].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [143]
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Metadata
- Authors
- Pastorino, L., Sun, A., Lu, P.-J., Zhou, X. Z., Balastik, M., Finn, G., Wulf, G., Lim, J., Li, S.-H., Li, X., Xia, W., Nicholson, L. K., & Lu, K. P.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Kaohsiung Veterans General Hospital (TW)
- Emory University (US)
- Brigham and Women's Hospital (US)
- Cornell University (US)
- Corresponding author
- Lu, Kun Ping
- ORCID
- Venue
- Nature
- Published
- 2006-03-23
- Volume
- 440
- Issue
- 7083
- Pages
- 528-534
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1974036368
- Cited by
- 487
- References
- 32
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 30 · 2023: 16 · 2022: 15 · 2021: 11 · 2020: 21 · 2019: 23 · 2018: 23 · 2017: 18 · 2016: 28 · 2015: 27 · 2014: 26 · 2013: 31 · 2012: 34
- FWCI
- 23.70
- Type
- journal article
- Language
- en
- Update notices
- erratum (2007-03-15)
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Science Foundation
- National Science Council
- National Institutes of Health
- National Institute on Aging (R01AG029385)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- peptidyl-prolyl isomerase, amyloid precursor protein, amyloid-beta production, Alzheimer's disease, cis-trans isomerization, APP phosphorylation, APP intracellular domain, tauopathy, neurofibrillary tangles, neuritic plaques, therapeutic target
- MeSH terms
- NIMA-Interacting Peptidylprolyl Isomerase, Alzheimer Disease, Animals, Catalysis, Cell Line, Cricetulus, Cricetinae, Humans, Phosphorylation, Protein Binding, Protein Processing, Post-Translational, Threonine, Transfection, Amyloid beta-Peptides, CHO Cells, Amyloid beta-Protein Precursor, Protein Structure, Tertiary, Mice, Knockout, Peptidylprolyl Isomerase, Cell Line, Tumor, Mice
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