Cited by 488Alzheimer's disease research and treatmentsSignaling Pathways in DiseaseNeuroinflammation and Neurodegeneration Mechanisms

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The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-β production

Pastorino, Lucia, Sun, Anyang, Lu, Pei-Jung, Zhou, Xiao Zhen, Balastik, Martin, Finn, Greg, Wulf, Gerburg, Lim, Jormay, Li, Shi-Hua, Li, Xiaojiang, Xia, Weiming, Nicholson, Linda K., Lu, Kun Ping·2006·Nature

DOI 10.1038/nature04543

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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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Self-citation

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: Sun, Anyang
Lu, Pei-Jung
Zhou, Xiao Zhen
Wulf, Gerburg
Lim, Jormay
Li, Xiaojiang
Xia, Weiming
Nicholson, Linda K.
Lu, Kun Ping
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2006-03-23
Volume: 440
Issue: 7083
Pages: 528-534
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature04543
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-β production

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