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Tau Kinetics in Neurons and the Human Central Nervous System
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We developed stable isotope labeling and mass spectrometry approaches to measure the kinetics of multiple isoforms and fragments of tau in the human central nervous system (CNS) and in human induced pluripotent stem cell (iPSC)-derived neurons. Newly synthesized tau is truncated and released from human neurons in 3 days. Although most tau proteins have similar turnover, 4R tau isoforms and phosphorylated forms of tau exhibit faster turnover rates, suggesting unique processing of these forms that may have independent biological activities. The half-life of tau in control human iPSC-derived neurons is 6.74 ± 0.45 days and in human CNS is 23 ± 6.4 days. In cognitively normal and Alzheimer's disease participants, the production rate of tau positively correlates with the amount of amyloid plaques, indicating a biological link between amyloid plaques and tau physiology.
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“One of the significant hurdles in modeling AD with iPSC-derived neurons or NGN2-induced neurons for the past decade has been their inability to produce the 4R Tau isoform found in adult human brains [19–22]; only the fetal 0N3R splicing isoform is produced, even after one year of differentiation [19].”
From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [22]
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“However, fetal neurons and iPSCs-derived neurons primarily express 3R-tau (20, 21)”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [21]
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“CSF tau species precede tau positron emission tomography (PET) abnormalities by a decade.18,19”
From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [19]
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“Thus, in relation to sporadic AD, this study adds further support to the hypothesis that CSF p-tau is closely related to Aβ-mediated tau release from neurons19 and challenges the notion of being simply a state marker of NFT.”
From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [19]
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“Sato et al36 report that in the human central nervous system, P-tau exhibits a faster turnover rate, which likely explains the elevated CSF level of this protein in various neurodegenerative conditions.”
From Association of Cognitive and Behavioral Features Between Adults With Tuberous Sclerosis and Frontotemporal Dementia (2020) · cites this paper as [36]
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“This is important because little 4R tau is expressed in induced pluripotent stem cell (iPSC)-derived models without a splice-site mutation (lovino et al., 2015; Sato et al., 2018; Sposito et al., 2015; Verheyen et al., 2018).”
From ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids (2021) · cites this paper as Sato et al., 2018
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“Instead, evidence now documents active secretion of tau in normal and disease conditions.19,65”
From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [19]
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Metadata
- Authors
- Sato, C., Barthélemy, N. R., Mawuenyega, K. G., Patterson, B. W., Gordon, B. A., Jockel-Balsarotti, J., Sullivan, M., Crisp, M. J., Kasten, T., Kirmess, K. M., Kanaan, N. M., Yarasheski, K. E., Baker-Nigh, A., Benzinger, T. L. S., Miller, T. M., Karch, C. M., & Bateman, R. J.
- Affiliations
- Washington University in St. Louis (US)
- Michigan State University (US)
- Corresponding author
- Sato, Chihiro
- Karch, Celeste M.
- Bateman, Randall J.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 97
- Issue
- 6
- Pages
- 1284-1298.e7
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC6137722
- OpenAlex
- W2794390181
- Cited by
- 586
- References
- 82
- Citations by year
- 2026: 44 · 2025: 64 · 2024: 60 · 2023: 68 · 2022: 84 · 2021: 90 · 2020: 81 · 2019: 70 · 2018: 24
- FWCI
- 45.72
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-05-16)
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 385 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- BrightFocus Foundation (A2014384S)
- Tau SILK Consortium
- NIH (R01NS095773, R01NS078398, K01 AG046374, P30DK056341, P01AG003991, UL1TR000448, P30NS098577, P01AG026276, K01 AG053474, P50AG005681, P41GM103422, P30DK020579)
- MetLife Foundation
- Knight ADRC (P50AG05681)
- Coins for Alzheimer’s Research Trust
- Barnes-Jewish Hospital Foundation (UL1TR002345)
- 41st Kanae Foundation for the Promotion of Science Fellowship
- McDonnell Science Grant for Neuroscience
- ALS Association (2427)
- DIAN-TU Pharma Consortium
- Tau Consortium
- Alzheimer’s Association Research Fellowship (AARF-16-443265)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- tau protein, tau isoforms, tau phosphorylation, 4R tau, iPSC-derived neurons, human central nervous system, amyloid plaques, Alzheimer's disease, stable isotope labeling
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Amino Acid Sequence, Brain, Cell Line, Cells, Cultured, Central Nervous System, Female, Humans, Kinetics, Male, Middle Aged, Biomarkers, tau Proteins, Induced Pluripotent Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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