Cited by 723Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAdvanced Proteomics Techniques and Applications

The DOI matches its Crossref record; 78 of the 78 references it cites were found in a registry or an index; none of the 34 sources its claims cite is checked for support yet.

Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease

Open access

Wesseling, Hendrik, Mair, Waltraud, Kumar, Mukesh, Schlaffner, Christoph N., Tang, Shaojun, Beerepoot, Pieter, Fatou, Benoit, Guise, Amanda J., Cheng, Long, Takeda, Shuko, Muntel, Jan, Rotunno, Melissa S., Dujardin, Simon, Davies, Peter, Kosik, Kenneth S., Miller, Bruce L., Berretta, Sabina, Hedreen, John C., Grinberg, Lea T., Seeley, William W., Hyman, Bradley T., Steen, Hanno, Steen, Judith A.·2020·Cell

DOI 10.1016/j.cell.2020.10.029PMC PMC8168922

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Abstract

SUMMARY To elucidate the role of Tau isoforms and post-translational modification (PTM) stoichiometry in Alzheimer’s disease (AD), we generated a high-resolution quantitative proteomics map of 95 PTMs on multiple isoforms of Tau isolated from postmortem human tissue from 49 AD and 42 control subjects. Although Tau PTM maps reveal heterogeneity across subjects, a subset of PTMs display high occupancy and frequency for AD, suggesting importance in disease. Unsupervised analyses indicate that PTMs occur in an ordered manner, leading to Tau aggregation. The processive addition and minimal set of PTMs associated with seeding activity was further defined by analysis of size-fractionated Tau. To summarize, features in the Tau protein critical for disease intervention at different stages of disease are identified, including enrichment of 0N and 4R isoforms, underrepresentation of the C terminus, an increase in negative charge in the proline-rich region (PRR), and a decrease in positive charge in the microtubule binding domain (MBD).

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TL;DR

This study used quantitative mass spectrometry to map tau post-translational modifications in postmortem brain from Alzheimer’s disease and control donors, finding heterogeneous but ordered modification patterns that track disease stage. It identifies isoform shifts and charge-related modifications linked to aggregation and seeding.

Key findings

Across 49 AD and 42 control subjects, 95 PTMs at 88 residues were mapped, including 55 phosphorylation, 17 ubiquitination, 19 acetylation, and 4 methylation sites; insoluble tau was about 100-fold higher in AD (~1,000 vs ~10 fmol/mg), while soluble tau was lower (~3,000 vs ~5,000 fmol/mg). Insoluble AD tau was enriched for 0N and 4R isoforms; N-terminal and C-terminal regions were underrepresented, proline-rich region phosphorylation was high, and microtubule-binding-domain acetylation/ubiquitination increased with aggregate size. Unsupervised clustering separated subjects into groups reflecting Braak stage and PTM burden, and a classifier trained on cohort 1 predicted AD pathology in cohort 2 with >0.92 accuracy. Size-fractionated tau showed seeding-competent high-molecular-weight/insoluble species had microtubule-binding-domain modifications and 20 phosphosites in the high-molecular-weight fraction, while seeding-incompetent low-molecular-weight/soluble species were N-terminally enriched and had fewer proline-rich-region phosphosites.

Methods

Postmortem BA39 angular gyrus from 49 AD and 42 matched controls was analyzed, plus BA46 frontal gyrus in 9 controls and 10 AD subjects; high- and low-molecular-weight tau fractions came from 4 AD and 4 control subjects. FLEXITau targeted mass spectrometry quantified absolute tau and isoform-specific peptides, while data-dependent LC-MS/MS mapped PTMs; sarkosyl solubility and size-exclusion/MC1 fractionation separated tau species. Analyses included PCA, hierarchical clustering, PLS-DA, Spearman correlation, and a stochastic gradient descent classifier; data were deposited in ProteomeXchange.

Limitations

Stated: using top-ranked PTMs as biomarkers requires an adequately powered study with suitable specimens, and high-molecular-weight fraction PTM patterns showed patient-to-patient variability. Stated/evident: the postmortem cross-sectional design cannot directly prove temporal order or causality of PTM progression, and some controls had early AD-like PTMs, complicating group boundaries. Evident: some analyses rely on small subsets (BA46 n=19; high-/low-molecular-weight n=8), and stoichiometry for some microtubule-binding-domain sites was around 50%, so not every tau molecule carries those modifications.

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Integrity signals

Registry

Crossref · 10.1016/j.cell.2020.10.029

Cites

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Probably not a substantial claim. 27
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In the paper
“we previously developed a targeted, high-throughput quantitative mass spectrometry (MS) method called FLEXITau (full-length expressed stable isotope-labeled Tau) (Mair et al., 2016), which provides absolute quantification and unbiased stoichiometric information of Tau PTMs from the N to the C terminus.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Mair et al., 2016
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In the paper
“Tau forms intracellular neurofibrillary tangles (NFTs) (Grundke-Iqbal et al., 1986; Kosik et al., 1986; Wood et al., 1986)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Grundke-Iqbal et al., 1986
- Not checked yetcites Kosik et al., 1986
- Not checked yetcites Wood et al., 1986
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Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Tens of possible PTM sites have been described for Tau in studies involving in vitro (Hanger et al., 2007; Martin et al., 2013a, 2013b) and in vivo AD mouse models (Morris et al., 2015; Tramutola et al., 2018) and in postmortem human studies (Hanger et al., 2007; Min et al., 2015).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Hanger et al., 2007
- Not checked yetcites Martin et al., 2013a
- Not checked yetcites Morris et al., 2015 source
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Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Besides phosphorylation, the neurofibrillary aggregates are also subject to a wide range of other PTMs (Hanger et al., 2007)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Hanger et al., 2007
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Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Aβ forms extracellular plaques (Glenner and Wong, 1984; Masters et al., 1985)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Glenner and Wong, 1984
- Not checked yetcites Masters et al., 1985
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“pathological neurofibrillary Tau aggregates show a pattern of accumulation that starts in the entorhinal cortex and spreads through connected pathways to cortical areas (Jucker and Walker, 2013)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Jucker and Walker, 2013 source
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The discovery of dominantly inherited Tau mutations leading to frontotemporal dementia (FTD) (Poorkaj et al., 1998; Spillantini et al., 1998)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Poorkaj et al., 1998 source
- Not checked yetcites Spillantini et al., 1998 source
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“brain lysates seed Tau aggregation when high-molecular-weight oligomeric hyperphosphorylated (AT8 and AT100) Tau species are present (Takeda et al., 2015; Jackson et al., 2016)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Takeda et al., 2015 source
- Not checked yetcites Jackson et al., 2016
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
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None of the sources cited for this claim have been checked yet.
In the paper
“Combinations of such PTMs are responsible for regulating and fine-tuning protein conformation and activity (Aebersold et al., 2018; Soria et al., 2014)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Aebersold et al., 2018 source
- Not checked yetcites Soria et al., 2014
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
Probably not a substantial claim.
In the paper
“This encompasses a cycle that involves production of a Tau seed followed by uptake of seed-competent Tau into connected cells (Clavaguera et al., 2013)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Clavaguera et al., 2013
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“which has been shown to form the core region of the Tau filaments (Fitzpatrick et al., 2017).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
What the sources say
- Not checked yetcites Fitzpatrick et al., 2017
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“which are known to regulate neurite extension and binding of Tau to microtubules (Biernat et al., 1993; Biernat and Mandelkow, 1999).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
What the sources say
- Not checked yetcites Biernat et al., 1993
- Not checked yetcites Biernat and Mandelkow, 1999
Strength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“an observation partially consistent with recent Tau PTM mapping results in mice (Morris et al., 2015; Table S5).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
What the sources say
- Not checked yetcites Morris et al., 2015 source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedn = 91
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, all MS/MS spectra of identified post-translationally modified peptides were subjected to manual verification.”
- Also stated in: § Preparation and MS analysis of MC1-isolated Tau · plain
  “Spectra for identified modified peptides were manually validated.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of high and low molecular weight Tau and mass spectrometric analysis
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“which would be charged positively at physiological pH and experience repulsive electrostatic forces, preventing formation of a b sheet fibril structure.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
Load-bearingStrength:hedged· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
- Rests on an assumption: Tau contains 19 lysine residues in its microtubule-binding domain.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“False discovery rate (FDR) was set to 1% on peptide and protein levels with a minimum length of seven amino acids and was determined by searching a reverse database.”
- Also stated in: § Preparation and MS analysis of MC1-isolated Tau · plain
  “False discovery rate (FDR) was set to 1% on peptide and protein level and was determined by searching a reverse database.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of brain tissue samples and mass spectrometry analysis
Load-bearingStrength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
Probably not a substantial claim. It may state two separate claims as one.

65 of 65

The authors state this as an assumption.
A qualitative and quantitative approach using a large cohort of human AD subjects had not been performed before this study.
“To our knowledge, a qualitative and quantitative approach using a large cohort of human AD subjects has not been performed.”
The authors state this as an assumption.
The minimum set of PTMs important for oligomer formation and Tau aggregation is not known.
“Furthermore, the minimum set of PTMs important for oligomer formation and Tau aggregation is not known.”
The authors state this as an assumption.
Which PTMs occur on Tau seeds that can potentiate further aggregation is not known.
“Finally, it is not known which PTMs occur on Tau seeds that can potentiate further aggregation.”
The paper relies on this without support.
Tau contains 19 lysine residues in its microtubule-binding domain.
“Tau has 19 lysine residues in the MBD”
The paper relies on this without support.
The disordered regions of Tau include the N terminus and the proline-rich region.
“The disordered regions of Tau span the N terminus and PRR.”
The paper relies on this without support.
HMW Tau is oligomeric Tau.
“HMW Tau, which is thought to be oligomeric Tau”

6 of 6

Claims other papers make about this one

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Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

Acetylation is both unique to seeding-positive Tau and present in seeding-incompetent Tau
Major
One passage says acetylation is unique to seeding-positive Tau relative to the seeding-negative fractions. The discussion instead says acetylation also occurs in seeding-incompetent Tau.
Residue 263 is identified as both serine and threonine
Minor
The results identify phosphorylation at S263 in one passage and T263 in another. The same numbered residue cannot have both identities in the Tau sequence being described.

2 of 2

Neuropathological stageing of Alzheimer-related changes.
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“Selected subjects had the least possible concurrent pathologies and were assessed for Braak NFT stages (Braak and Braak, 1991), as determined by the location of NFTs with total Tau immunostaining and Bielschowsky’s silver stain.”
BackgroundMethod
MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification
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Method
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Method
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Background
Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ
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Method
The Consortium to Establish a Registry for Alzheimer's Disease (CERAD): Part II. Standardization of the neuropathologic assessment of Alzheimer's disease
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Method
Skyline: an open source document editor for creating and analyzing targeted proteomics experiments
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“Aβ forms extracellular plaques (Glenner and Wong, 1984; Masters et al., 1985), whereas Tau forms intracellular neurofibrillary tangles (NFTs) (Grundke-Iqbal et al.”
Background
Tau in physiology and pathology
Wang, Y., & Mandelkow, E. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2015.1 · Cited by 2,251 · cited 1×
“The mechanistic role of PTMs in initiating Tau seeding and propagation still remains to be elucidated (Guo et al., 2017; Wang and Mandelkow, 2016).”
Background
Cryo-EM structures of tau filaments from Alzheimer’s disease
Fitzpatrick, A. W. P., Falcon, B., He, S., Murzin, A. G., Murshudov, G., Garringer, H. J., Crowther, R. A., Ghetti, B., Goedert, M., & Scheres, S. H. W. (2017) · Nature · doi:10.1038/nature23002 · Cited by 2,061 · cited 2×
“Sixteen of 17 identified ubiquitination sites are in the microtubule binding domain (MBD), which forms the core of the filament (Crowther et al., 1989; Falcon et al., 2018; Fitzpatrick et al., 2017).”
Background
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Self-propagation of pathogenic protein aggregates in neurodegenerative diseases
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“During disease progression in AD, pathological neurofibrillary Tau aggregates show a pattern of accumulation that starts in the entorhinal cortex and spreads through connected pathways to cortical areas (Jucker and Walker, 2013).”
Background
Proteoform: a single term describing protein complexity
The Consortium for Top Down Proteomics, Smith, L. M., & Kelleher, N. L. (2013) · Nature Methods · doi:10.1038/nmeth.2369 · Cited by 1,528
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“, 1985), whereas Tau forms intracellular neurofibrillary tangles (NFTs) (Grundke-Iqbal et al., 1986; Kosik et al., 1986; Wood et al., 1986).”
BackgroundSelf-citation
Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease
Gómez‐Isla, T., Hollister, R., West, H., Mui, S., Growdon, J. H., Petersen, R. C., Parisi, J. E., & Hyman, B. T. (1997) · Annals of Neurology · doi:10.1002/ana.410410106 · Cited by 1,489 · cited 1×
“, 1998) and correlation of Tau pathology with cognitive decline in AD (Arriagada et al., 1992; Bierer et al., 1995; Giannakopoulos et al., 2003; Gómez-Isla et al., 1997) have led to several mechanistic studies whose outcomes have underscored the importance of Tau in AD and other dementias (Mudher et al.”
BackgroundSelf-citation
Mutation in the tau gene in familial multiple system tauopathy with presenile dementia
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“The discovery of dominantly inherited Tau mutations leading to frontotemporal dementia (FTD) (Poorkaj et al., 1998; Spillantini et al., 1998) and correlation of Tau pathology with cognitive decline in AD (Arriagada et al., 1992; Bierer et al., 1995; Giannakopoulos et al., 2003; Gómez-Isla et al., 1997) have led to sev…”
BackgroundInfluential
Propagation of Tau Pathology in a Model of Early Alzheimer's Disease
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Self-citation
Tau is a candidate gene for chromosome 17 frontotemporal dementia
Poorkaj, P., Bird, T. D., Wijsman, E., Nemens, E., Garruto, R. M., Anderson, L., Andreadis, A., Wiederholt, W. C., Raskind, M., & Schellenberg, G. D. (1998) · Annals of Neurology · doi:10.1002/ana.410430617 · Cited by 1,374 · cited 4×
“The discovery of dominantly inherited Tau mutations leading to frontotemporal dementia (FTD) (Poorkaj et al., 1998; Spillantini et al., 1998) and correlation of Tau pathology with cognitive decline in AD (Arriagada et al., 1992; Bierer et al., 1995; Giannakopoulos et al., 2003; Gómez-Isla et al., 1997) have led to sev…”
BackgroundInfluential
Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia
Janelidze, S., Mattsson, N., Palmqvist, S., Smith, R., Beach, T. G., Serrano, G. E., Chai, X., Proctor, N. K., Eichenlaub, U., Zetterberg, H., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0755-1 · Cited by 1,247 · cited 2×
“The 16 asymptomatic patients display increased phosphorylation of the PRR, such as T181, which has been reported to be increased in antemortem plasma of individuals with mild cognitive impairment (MCI) (Janelidze et al., 2020; Thijssen et al., 2020).”
Background
pcaMethods—a bioconductor package providing PCA methods for incomplete data
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BackgroundMethodInfluential
Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease
Giannakopoulos, P., Herrmann, F. R., Bussière, T., Bouras, C., Kövari, E., Perl, D. P., Morrison, J. H., Gold, G., & Hof, P. R. (2003) · Neurology · doi:10.1212/01.wnl.0000063311.58879.01 · Cited by 1,118 · cited 1×
“, 1998) and correlation of Tau pathology with cognitive decline in AD (Arriagada et al., 1992; Bierer et al., 1995; Giannakopoulos et al., 2003; Gómez-Isla et al., 1997) have led to several mechanistic studies whose outcomes have underscored the importance of Tau in AD and other dementias (Mudher et al.”
Background
Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans
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“To overcome these electrostatic forces and promote aggregation, charge neutralization of the MBD is required, and anionic experimental cofactor models have been described to promote aggregation: heparin (Goedert et al., 1996; Fichou et al., 2018) and RNA or its associated granules (Kampers et al.”
Lysine Acetylation: Codified Crosstalk with Other Posttranslational Modifications
Yang, X.-J., & Seto, E. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.07.002 · Cited by 1,006 · cited 1×
“Consistent with previous biochemical studies in mice (Morris et al., 2015; Yang and Seto, 2008), most of the human Tau acetylation sites identified were ubiquitinated alternatively (Figure 1E).”
Result
Roles of tau protein in health and disease
Guo, T., Noble, W., & Hanger, D. P. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1707-9 · Cited by 1,003 · cited 1×
“The mechanistic role of PTMs in initiating Tau seeding and propagation still remains to be elucidated (Guo et al., 2017; Wang and Mandelkow, 2016).”
Background
Acetylation of Tau Inhibits Its Degradation and Contributes to Tauopathy
Min, S.-W., Cho, S.-H., Zhou, Y., Schroeder, S., Haroutunian, V., Seeley, W. W., Huang, E. J., Shen, Y., Masliah, E., Mukherjee, C., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.08.044 · Cited by 949 · cited 4×
“The discovery of dominantly inherited Tau mutations leading to frontotemporal dementia (FTD) (Poorkaj et al., 1998; Spillantini et al., 1998) and correlation of Tau pathology with cognitive decline in AD (Arriagada et al., 1992; Bierer et al., 1995; Giannakopoulos et al., 2003; Gómez-Isla et al., 1997) have led to sev…”
BackgroundInfluentialSelf-citation
How many human proteoforms are there?
Aebersold, R., Agar, J. N., Amster, I. J., Baker, M. S., Bertozzi, C. R., Boja, E. S., Costello, C. E., Cravatt, B. F., Fenselau, C., Garcia, B. A., et al. (2018) · Nature Chemical Biology · doi:10.1038/nchembio.2576 · Cited by 907 · cited 1×
“Combinations of such PTMs are responsible for regulating and fine-tuning protein conformation and activity (Aebersold et al., 2018; Soria et al., 2014) and can dramatically change the function and toxicity of proteins.”
Background
Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding
Bramblett, G. T., Goedert, M., Jakes, R., Merrick, S. E., Trojanowski, J. Q., & Lee, V. M. Y. (1993) · Neuron · doi:10.1016/0896-6273(93)90057-x · Cited by 903 · cited 4×
“The discovery of dominantly inherited Tau mutations leading to frontotemporal dementia (FTD) (Poorkaj et al., 1998; Spillantini et al., 1998) and correlation of Tau pathology with cognitive decline in AD (Arriagada et al., 1992; Bierer et al., 1995; Giannakopoulos et al., 2003; Gómez-Isla et al., 1997) have led to sev…”
BackgroundInfluential
Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly
Cleveland, D. W., Hwo, S. Y., & Kirschner, M. W. (1977) · Journal of Molecular Biology · doi:10.1016/0022-2836(77)90214-5 · Cited by 881 · cited 1×
“Since the discovery of phosphorylation and the first description of isoforms of Tau (Cleveland et al., 1977), the roles of Tau proteoforms (different chemical versions of a polypeptide) have been explored functionally (Adams et al.”
Background
Hyperphosphorylation induces self-assembly of τ into tangles of paired helical filaments/straight filaments
Alonso, A. D. C., Zaidi, T., Novak, M., Grundke-Iqbal, I., & Iqbal, K. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.121119298 · Cited by 827 · cited 1×
“Thus, it has been hypothesized that the types of PTMs, their site-specific localization, and their extent of modification induce or mediate Tau aggregation and propagation (Cohen et al., 2011; Alonso et al., 2001).”
Background
Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: Distinction between PHF-like immunoreactivity and microtubule binding
Biernat, J., Gustke, N., Drewes, G., Mandelkow, E., & Mandelkow, E. (1993) · Neuron · doi:10.1016/0896-6273(93)90279-z · Cited by 796 · cited 1×
“These sites include three KXGS motifs, which are known to regulate neurite extension and binding of Tau to microtubules (Biernat et al., 1993; Biernat and Mandelkow, 1999).”
Background
Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau)
Wood, J. G., Mirra, S. S., Pollock, N. J., & Binder, L. I. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.11.4040 · Cited by 763 · cited 1×
“, 1985), whereas Tau forms intracellular neurofibrillary tangles (NFTs) (Grundke-Iqbal et al., 1986; Kosik et al., 1986; Wood et al., 1986).”
Background
Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration
Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) investigators, Thijssen, E. H., La Joie, R., Wolf, A., Strom, A., Wang, P., Iaccarino, L., Bourakova, V., Cobigo, Y., Heuer, H., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0762-2 · Cited by 761
Self-citation
The acetylation of tau inhibits its function and promotes pathological tau aggregation
Cohen, T. J., Guo, J. L., Hurtado, D. E., Kwong, L. K., Mills, I. P., Trojanowski, J. Q., & Lee, V. M. Y. (2011) · Nature Communications · doi:10.1038/ncomms1255 · Cited by 724 · cited 1×
“Thus, it has been hypothesized that the types of PTMs, their site-specific localization, and their extent of modification induce or mediate Tau aggregation and propagation (Cohen et al., 2011; Alonso et al., 2001).”
Background
Proteopathic tau seeding predicts tauopathy in vivo
Holmes, B. B., Furman, J. L., Mahan, T. E., Yamasaki, T. R., Mirbaha, H., Eades, W. C., Belaygorod, L., Cairns, N. J., Holtzman, D. M., & Diamond, M. I. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1411649111 · Cited by 696 · cited 1×
“These Tau fractions do not have positive seeding activity in biosensor assays (Holmes et al., 2014; Takeda et al., 2015).”
Background
Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease
Arriagada, P. V., Marzloff, K., & Hyman, B. T. (1992) · Neurology · doi:10.1212/wnl.42.9.1681 · Cited by 638 · cited 1×
“, 1998) and correlation of Tau pathology with cognitive decline in AD (Arriagada et al., 1992; Bierer et al., 1995; Giannakopoulos et al., 2003; Gómez-Isla et al., 1997) have led to several mechanistic studies whose outcomes have underscored the importance of Tau in AD and other dementias (Mudher et al.”
BackgroundSelf-citation
Tau protein kinases: Involvement in Alzheimer's disease
Martin, L., Latypova, X., Wilson, C. M., Magnaudeix, A., Perrin, M.-L., Yardin, C., & Terro, F. (2013) · Ageing Research Reviews · doi:10.1016/j.arr.2012.06.003 · Cited by 631
Tau and tauopathies
Arendt, T., Stieler, J. T., & Holzer, M. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.08.018 · Cited by 609 · cited 2×
“Although 86 phosphorylation events have been described on Tau in general (Arendt et al., 2016) (i.”
Background
Monoclonal antibody AT8 recognises tau protein phosphorylated at both serine 202 and threonine 205
Goedert, M., Jakes, R., & Vanmechelen, E. (1995) · Neuroscience Letters · doi:10.1016/0304-3940(95)11484-e · Cited by 608 · cited 1×
“In some control subjects, these phosphopeptides are further phosphorylated and show some of the same PTMs associated with pathological Tau (Goedert et al., 1995).”
Background
Using i RT , a normalized retention time for more targeted measurement of peptides
Escher, C., Reiter, L., MacLean, B., Ossola, R., Herzog, F., Chilton, J. M., MacCoss, M. J., & Rinner, O. (2012) · PROTEOMICS · doi:10.1002/pmic.201100463 · Cited by 597 · cited 1×
“Vacuumdried peptides were reconstituted in sample buffer (5% formic acid, 5% acetonitrile (ACN)) containing indexed retention time (iRT) peptides (Biognosys) (Escher et al., 2012) and 10 fmol/μl non-labeled FLEX-peptide and 100 fmol/ul heavy-isotope labeled isoform specific peptides (AEEAGIGDTPSL[+7.”
Method
Proline-directed and non-proline-directed phosphorylation of PHF-tau
Morishima-Kawashima, M., Hasegawa, M., Takio, K., Suzuki, M., Yoshida, H., Titani, K., & Ihara, Y. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.2.823 · Cited by 557 · cited 1×
“, in vivo, in vitro, and across different organisms and model systems), and over 31 phosphorylation sites have been identified to be associated with physiological functions (Hasegawa et al., 1992; Lovestone and Reynolds, 1997; Morishima Kawashima et al., 1995), only 45 Tau phosphorylation events have so far been descr…”
Background
RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments
Kampers, T., Friedhoff, P., Biernat, J., Mandelkow, E.-M., & Mandelkow, E. (1996) · FEBS Letters · doi:10.1016/s0014-5793(96)01386-5 · Cited by 548 · cited 1×
“, 2018) and RNA or its associated granules (Kampers et al., 1996; Zhang et al., 2017; Dinkel et al., 2015).”
Background
Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits
Min, S.-W., Chen, X., Tracy, T. E., Li, Y., Zhou, Y., Wang, C., Shirakawa, K., Minami, S. S., Defensor, E., Mok, S. A., et al. (2015) · Nature Medicine · doi:10.1038/nm.3951 · Cited by 516 · cited 1×
“, 2018) and in postmortem human studies (Hanger et al., 2007; Min et al., 2015).”
Background
Neocortical Neurofibrillary Tangles Correlate With Dementia Severity in Alzheimer's Disease
Bierer, L. M., Hof, P. R., Purohit, D. P., Carlin, L., Schmeidler, J., Davis, K. L., & Perl, D. P. (1995) · Archives of Neurology · doi:10.1001/archneur.1995.00540250089017 · Cited by 514 · cited 1×
“, 1998) and correlation of Tau pathology with cognitive decline in AD (Arriagada et al., 1992; Bierer et al., 1995; Giannakopoulos et al., 2003; Gómez-Isla et al., 1997) have led to several mechanistic studies whose outcomes have underscored the importance of Tau in AD and other dementias (Mudher et al.”
Background
Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice
Morris, M., Knudsen, G. M., Maeda, S., Trinidad, J. C., Ioanoviciu, A., Burlingame, A. L., & Mucke, L. (2015) · Nature Neuroscience · doi:10.1038/nn.4067 · Cited by 472 · cited 2×
“Consistent with previous biochemical studies in mice (Morris et al., 2015; Yang and Seto, 2008), most of the human Tau acetylation sites identified were ubiquitinated alternatively (Figure 1E).”
BackgroundResult
Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis
Hanger, D. P., Byers, H. L., Wray, S., Leung, K.-Y., Saxton, M. J., Seereeram, A., Reynolds, C. H., Ward, M. A., & Anderton, B. H. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m703269200 · Cited by 455 · cited 3×
“Besides phosphorylation, the neurofibrillary aggregates are also subject to a wide range of other PTMs (Hanger et al., 2007).”
Background
Global Hairpin Folding of Tau in Solution
Jeganathan, S., von Bergen, M., Brutlach, H., Steinhoff, H.-J., & Mandelkow, E. (2006) · Biochemistry · doi:10.1021/bi0521543 · Cited by 432 · cited 2×
“neutralizing positive charges of the MBD lysines by folding back on the MBD in a modified version of the previously described hairpin structure (Jeganathan et al., 2006), where the phosphorylated C terminus and phosphorylated PRR domain stabilize the positive charge of the MBD.”
Background
Protein sequence and mass spectrometric analyses of tau in the Alzheimer's disease brain
Hasegawa, M., Morishima-Kawashima, M., Takio, K., Suzuki, M., Titani, K., & Ihara, Y. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)41890-x · Cited by 430 · cited 1×
“, in vivo, in vitro, and across different organisms and model systems), and over 31 phosphorylation sites have been identified to be associated with physiological functions (Hasegawa et al., 1992; Lovestone and Reynolds, 1997; Morishima Kawashima et al., 1995), only 45 Tau phosphorylation events have so far been descr…”
Background
What is the evidence that tau pathology spreads through prion-like propagation?
Mudher, A., Colin, M., Dujardin, S., Medina, M., Dewachter, I., Alavi Naini, S. M., Mandelkow, E.-M., Mandelkow, E., Buée, L., Goedert, M., et al. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0488-7 · Cited by 384 · cited 1×
“…of Tau pathology with cognitive decline in AD (Arriagada et al., 1992; Bierer et al., 1995; Giannakopoulos et al., 2003; Gómez-Isla et al., 1997) have led to several mechanistic studies whose outcomes have underscored the importance of Tau in AD and other dementias (Mudher et al., 2017).”
ResultSelf-citation
Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain
Takeda, S., Wegmann, S., Cho, H., DeVos, S. L., Commins, C., Roe, A. D., Nicholls, S. B., Carlson, G. A., Pitstick, R., Nobuhara, C. K., et al. (2015) · Nature Communications · doi:10.1038/ncomms9490 · Cited by 371 · cited 8×
“It has been suggested that brain lysates seed Tau aggregation when high-molecular-weight oligomeric hyperphosphorylated (AT8 and AT100) Tau species are present (Takeda et al., 2015; Jackson et al., 2016).”
BackgroundMethodInfluentialSelf-citation
Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold
Falcon, B., Zhang, W., Schweighauser, M., Murzin, A. G., Vidal, R., Garringer, H. J., Ghetti, B., Scheres, S. H. W., & Goedert, M. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1914-z · Cited by 362 · cited 1×
“Sixteen of 17 identified ubiquitination sites are in the microtubule binding domain (MBD), which forms the core of the filament (Crowther et al., 1989; Falcon et al., 2018; Fitzpatrick et al., 2017).”
Background
RNA stores tau reversibly in complex coacervates
Zhang, X., Lin, Y., Eschmann, N. A., Zhou, H., Rauch, J. N., Hernández, I., Guzman, E., Kosik, K. S., & Han, S. (2017) · PLoS Biology · doi:10.1371/journal.pbio.2002183 · Cited by 312 · cited 1×
“, 2018) and RNA or its associated granules (Kampers et al., 1996; Zhang et al., 2017; Dinkel et al., 2015).”
BackgroundSelf-citation
Discussion
Lovestone, S., & Reynolds, C. H. (1997) · Neuroscience · doi:10.1016/s0306-4522(96)00577-5 · Cited by 278 · cited 1×
“, in vivo, in vitro, and across different organisms and model systems), and over 31 phosphorylation sites have been identified to be associated with physiological functions (Hasegawa et al., 1992; Lovestone and Reynolds, 1997; Morishima Kawashima et al., 1995), only 45 Tau phosphorylation events have so far been descr…”
Background
Tau protein phosphatases in Alzheimer's disease: The leading role of PP2A
Martin, L., Latypova, X., Wilson, C. M., Magnaudeix, A., Perrin, M.-L., & Terro, F. (2012) · Ageing Research Reviews · doi:10.1016/j.arr.2012.06.008 · Cited by 265
Mechanisms of Protein Seeding in Neurodegenerative Diseases
Walker, L. C., Diamond, M. I., Duff, K. E., & Hyman, B. T. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.1453 · Cited by 226 · cited 2×
“During disease progression in AD, pathological neurofibrillary Tau aggregates show a pattern of accumulation that starts in the entorhinal cortex and spreads through connected pathways to cortical areas (Jucker and Walker, 2013).”
BackgroundSelf-citation
cAMP-Dependent Protein Kinase Phosphorylations on Tau in Alzheimer’s Disease
Jicha, G. A., Weaver, C. L., Lane, E., Vianna, C., Kress, Y., Rockwood, J. M., & Davies, P. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-17-07486.1999 · Cited by 207
Self-citation
Short Fibrils Constitute the Major Species of Seed-Competent Tau in the Brains of Mice Transgenic for Human P301S Tau
Jackson, S. J., Kerridge, C., Cooper, J., Cavallini, A., Falcon, B., Cella, C. V., Landi, A., Szekeres, P. G., Murray, T. K., Ahmed, Z., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.3542-15.2016 · Cited by 163 · cited 1×
“It has been suggested that brain lysates seed Tau aggregation when high-molecular-weight oligomeric hyperphosphorylated (AT8 and AT100) Tau species are present (Takeda et al., 2015; Jackson et al., 2016).”
Background
The Development of Cell Processes Induced by tau Protein Requires Phosphorylation of Serine 262 and 356 in the Repeat Domain and Is Inhibited by Phosphorylation in the Proline-rich Domains
Biernat, J., & Mandelkow, E.-M. (1999) · Molecular Biology of the Cell · doi:10.1091/mbc.10.3.727 · Cited by 149 · cited 1×
“These sites include three KXGS motifs, which are known to regulate neurite extension and binding of Tau to microtubules (Biernat et al., 1993; Biernat and Mandelkow, 1999).”
Background
FLEXITau: Quantifying Post-translational Modifications of Tau Protein in Vitro and in Human Disease
Mair, W., Muntel, J., Tepper, K., Tang, S., Biernat, J., Seeley, W. W., Kosik, K. S., Mandelkow�, E., Steen, H., & Steen, J. A. J. (2016) · Analytical Chemistry · doi:10.1021/acs.analchem.5b04509 · Cited by 144 · cited 5×
“To quantify absolute Tau amounts and determine the extent of Tau PTMs, sarkosyl-insoluble and soluble fractions were processed using the FLEXITau workflow as previously described (Mair et al., 2016).”
BackgroundMethodInfluentialSelf-citation
“Prion‐Like” Templated Misfolding in Tauopathies
Clavaguera, F., Lavenir, I., Falcon, B., Frank, S., Goedert, M., & Tolnay, M. (2013) · Brain Pathology · doi:10.1111/bpa.12044 · Cited by 133 · cited 1×
“This encompasses a cycle that involves production of a Tau seed followed by uptake of seed-competent Tau into connected cells (Clavaguera et al., 2013).”
Background
Cofactors are essential constituents of stable and seeding-active tau fibrils
Fichou, Y., Lin, Y., Rauch, J. N., Vigers, M., Zeng, Z., Srivastava, M., Keller, T. J., Freed, J. H., Kosik, K. S., & Han, S. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1810058115 · Cited by 128 · cited 1×
“To overcome these electrostatic forces and promote aggregation, charge neutralization of the MBD is required, and anionic experimental cofactor models have been described to promote aggregation: heparin (Goedert et al., 1996; Fichou et al., 2018) and RNA or its associated granules (Kampers et al.”
Background
FLEXIQuant: A Novel Tool for the Absolute Quantification of Proteins, and the Simultaneous Identification and Quantification of Potentially Modified Peptides
Singh, S. A., Springer, M., Steen, J. A. J., Kirschner, M. W., & Steen, H. (2009) · Journal of Proteome Research · doi:10.1021/pr800654s · Cited by 113 · cited 1×
“Absolute abundance of Tau was calculated using the FLEX peptide L/H ratio as described before (Singh et al., 2009).”
MethodSelf-citation
Multisite assessment of NIA‐AA guidelines for the neuropathologic evaluation of Alzheimer's disease
Montine, T. J., Monsell, S. E., Beach, T. G., Bigio, E. H., Bu, Y., Cairns, N. J., Frosch, M., Henriksen, J., Kofler, J., Kukull, W. A., et al. (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2015.07.492 · Cited by 113 · cited 2×
“Inclusion in the study required a highconfidence postmortem neuropathological diagnosis of AD, based on relevant criteria (Montine et al., 2016; Mirra et al., 1991), for the clinical AD group or no more than low AD neuropathological change (Montine et al.”
BackgroundMethodSelf-citation
Three Repeat Isoforms of Tau Inhibit Assembly of Four Repeat Tau Filaments
Adams, S. J., Deture, M. A., McBride, M., Dickson, D. W., & Petrucelli, L. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010810 · Cited by 110 · cited 1×
“, 1977), the roles of Tau proteoforms (different chemical versions of a polypeptide) have been explored functionally (Adams et al., 2010), and many of these studies have highlighted the importance of post-translational modifications (PTMs) of Tau in AD and FTD (Bramblett et al.”
Background
The Repeat Region of Microtubule-Associated Protein Tau Forms Part of the Core of the Paired Helical Filament of Alzheimer's Disease
Crowther, T., Goedert, M., & Wischik, C. M. (1989) · Annals of Medicine · doi:10.3109/07853898909149199 · Cited by 107 · cited 1×
“Sixteen of 17 identified ubiquitination sites are in the microtubule binding domain (MBD), which forms the core of the filament (Crowther et al., 1989; Falcon et al., 2018; Fitzpatrick et al., 2017).”
Background
RNA Binds to Tau Fibrils and Sustains Template-Assisted Growth
Dinkel, P. D., Holden, M. R., Matin, N., & Margittai, M. (2015) · Biochemistry · doi:10.1021/acs.biochem.5b00453 · Cited by 85 · cited 1×
“, 2018) and RNA or its associated granules (Kampers et al., 1996; Zhang et al., 2017; Dinkel et al., 2015).”
Background
Quantitative Analysis of the Brain Ubiquitylome in Alzheimer's Disease
Abreha, M. H., Dammer, E. B., Ping, L., Zhang, T., Duong, D. M., Gearing, M., Lah, J. J., Levey, A. I., & Seyfried, N. T. (2018) · PROTEOMICS · doi:10.1002/pmic.201800108 · Cited by 82 · cited 1×
“A total of 28 ubiquitination sites have been identified previously on Tau extracted from postmortem AD brain total lysates using ubiquitination enrichment (Abreha et al., 2018).”
Background
Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1
Sigurdsson, E. M. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179937 · Cited by 76 · cited 2×
“1% of all antibodies can cross the blood-brain barrier (BBB), increasing the specificity and affinity of the intended therapeutic antibody for the pathologic form of Tau is essential for successful therapy (Sigurdsson, 2018).”
BackgroundInfluential
Co‐regulation proteomics reveals substrates and mechanisms of APC/C‐dependent degradation
Singh, S., Winter, D., Kirchner, M., Chauhan, R. S., Ahmed, S. S. E.-D., Özlü, N., Tzur, A., van der Steen, J. A., & Steen, H. (2014) · The EMBO Journal · doi:10.1002/embj.201385876 · Cited by 73 · cited 1×
“Although several PTMs are present at basal levels in cells, not all of these are functionally significant in the context of specific pathological conditions (Singh et al., 2014).”
BackgroundSelf-citation
Hierarchical Phosphorylation of Recombinant Tau by the Paired‐Helical Filament‐Associated Protein Kinase Is Dependent on Cyclic AMP‐Dependent Protein Kinase
Jicha, G. A., Donnell, A. O., Weaver, C., Angeletti, R., & Davies, P. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0720214.x · Cited by 71
Self-citation
When less can yield more – Computational preprocessing of MS/MS spectra for peptide identification
Renard, B. Y., Kirchner, M., Monigatti, F., Ivanov, A. R., Rappsilber, J., Winter, D., Steen, J. A. J., Hamprecht, F. A., & Steen, H. (2009) · PROTEOMICS · doi:10.1002/pmic.200900326 · Cited by 70 · cited 1×
“, 2008) The spectra were centroided and filtered using ms2preproc to select the 6 most intense peaks in a 30 Th window (Renard et al., 2009).”
MethodSelf-citation
Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls
Sigurdsson, E. M. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-189010 · Cited by 67
Functional Divergence for Every Paralog
Soria, P. S., McGary, K. L., & Rokas, A. (2014) · Molecular Biology and Evolution · doi:10.1093/molbev/msu050 · Cited by 55 · cited 1×
“Combinations of such PTMs are responsible for regulating and fine-tuning protein conformation and activity (Aebersold et al., 2018; Soria et al., 2014) and can dramatically change the function and toxicity of proteins.”
Background
Proteomic identification of altered protein O-GlcNAcylation in a triple transgenic mouse model of Alzheimer's disease
Tramutola, A., Sharma, N. K., Barone, E., Lanzillotta, C., Castellani, A., Iavarone, F., Vincenzoni, F., Castagnola, M., Butterfield, D. A., Gaetani, S., et al. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.07.017 · Cited by 44 · cited 2×
“, 2013a, 2013b) and in vivo AD mouse models (Morris et al., 2015; Tramutola et al., 2018) and in postmortem human studies (Hanger et al.”
Background
Tau Imaging in Alzheimer's Disease Diagnosis and Clinical Trials
Brosch, J. R., Farlow, M. R., Risacher, S. L., & Apostolova, L. G. (2016) · Neurotherapeutics · doi:10.1007/s13311-016-0490-y · Cited by 37 · cited 1×
“For example, to develop a Tau PET radiotracer for detection of disease before cognitive decline, the chemical composition and abundance of pathological species at early disease stages is essential (Brosch et al., 2017).”
Background

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Self-citation
Applications of multi‐omics analysis in human diseases
Chen, C., Wang, J., Pan, D., Wang, X., Xu, Y., Yan, J., Wang, L., Yang, X., Yang, M., & Liu, G. (2023) · MedComm · doi:10.1002/mco2.315 · Cited by 545

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Authors: Wesseling, H., Mair, W., Kumar, M., Schlaffner, C. N., Tang, S., Beerepoot, P., Fatou, B., Guise, A. J., Cheng, L., Takeda, S., Muntel, J., Rotunno, M. S., Dujardin, S., Davies, P., Kosik, K. S., Miller, B. L., Berretta, S., Hedreen, J. C., Grinberg, L. T., Seeley, W. W., Hyman, B. T., Steen, H., & Steen, J. A.
Affiliations: Boston Children's Hospital (US)
Harvard University (US)
Feinstein Institute for Medical Research (US)
University of California, Santa Barbara (US)
University of California, San Francisco (US)
Corresponding author: Steen, Judith A.
ORCID: Kumar, Mukesh
Schlaffner, Christoph N.
Tang, Shaojun
Beerepoot, Pieter
Fatou, Benoit
Guise, Amanda J.
Cheng, Long
Takeda, Shuko
Muntel, Jan
Dujardin, Simon
Davies, Peter
Kosik, Kenneth S.
Miller, Bruce L.
Berretta, Sabina
Hedreen, John C.
Grinberg, Lea T.
Seeley, William W.
Hyman, Bradley T.
Steen, Hanno
Steen, Judith A.
Venue: Cell
Publisher: Elsevier BV
Published: 2020-12
Volume: 183
Issue: 6
Pages: 1699-1713.e13
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2020.10.029
PMC: PMC8168922
OpenAlex: W3102160053
Semantic Scholar: eb7657dfe7b98f7376299bf9d45805d3dc70eb6d
Cited by: 688
References: 78
Citations by year: 2026: 104 · 2025: 132 · 2024: 140 · 2023: 112 · 2022: 109 · 2021: 88 · 2020: 2
FWCI: 47.08
Type: journal article
Language: en
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, 374 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: National Institutes of Health
Tau Consortium
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: Alzheimer's disease, tau protein, post-translational modification, tau isoforms, tau aggregation, seeding activity, patient heterogeneity, disease staging, proline-rich region, microtubule-binding domain, postmortem brain, quantitative proteomics
MeSH terms: Alzheimer Disease, Humans, Protein Processing, Post-Translational, Cohort Studies, Case-Control Studies, tau Proteins, Disease Progression, Protein Isoforms, Principal Component Analysis

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Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease

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