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Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease
Open accessAbstract
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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96 Own result · 35 Own interpretation · 19 Not checked yet · 14 Own method · 2 No basis given
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“Our analysis extended this to 55 phosphorylation sites on pathological insoluble Tau in BA39 and 43 phosphosites in B46 (Figure S2C).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
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“The median concentrations of pathological insoluble Tau in BA39 were 100-fold higher in AD (~1,000 fmol/mg fresh weight of tissue) compared with controls (~10 fmol/mg fresh weight of tissue) (Figure 1B).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Concentrations and Isoform Distributions in AD and Control Subjects
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“Interestingly, in soluble Tau, the most abundant species are the 1N and 4R isoforms”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Concentrations and Isoform Distributions in AD and Control Subjects
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“underrepresentation of the C terminus”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > Abstract
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“The data and subsequent analyses showed that that the highest-frequency PTMs, isoform distributions, and quantitative profiles of the BA46 region are shared between the two brain regions”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS
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“subjects in these clusters have a significantly higher Tau and amyloid burden in BA39 than subjects falling into clusters a and d (Figure 2B).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“Increased phosphorylation of the PRR is also observed in symptomatic patients in cluster d as well as in AD clusters b and c”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“Although Tau PTM maps reveal heterogeneity across subjects”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > Abstract
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“The total amount of soluble Tau is lower in AD patients (~3,000 fmol/mg fresh weight of tissue) compared with control subjects (~5,000 fmol/mg fresh weight of tissue) (Figure 1B).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Concentrations and Isoform Distributions in AD and Control Subjects
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“In particular, the peptides spanning [195–209] and [212–224] that encompass the sites (S198, S199, S202, T205) and (S212, S214, S217) respectively, are observed to be > 90% modified in AD in the FLEXITau data.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
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“Cluster d contains 10 symptomatic patients with late stage AD pathology Braak IV-VI and 16 asymptomatic controls at Braak 0–II.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“ANOVA analysis showed higher Tau and Ab levels in clusters with a higher Braak stage and increased level of Tau PTMs (Figure 2B).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“We identified 95 distinct PTMs on 88 amino acid residues across all samples and fractions, with a cumulative sequence coverage of 96% from detected modified and unmodified 2N4R Tau peptides (Figure 1E).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
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“Some of the 88 sites of modification mapped are modified by a single type of PTM; however, others can carry multiple types of modifications, such as K311, which can be ubiquitinated or acetylated.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
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“In this study, we show that 17 ubiquitin sites are specific to pathological Tau (14 in BA46; Figure S2C).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
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“A large percentage of AD patients cluster into two major groups (Figure 2A, b and c), whereas the controls fall into two clusters (Figure 2A, a and d).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“Instead, the 1N isoform is depleted significantly, and the 0N isoform is enriched in the insoluble fraction.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Concentrations and Isoform Distributions in AD and Control Subjects
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“FLEXITau quantified a total of 24 Tau peptides; of these, some were isoform specific, achieving a total sequence coverage of 61% for the 2N4R Tau isoform (Figure 1D).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Concentrations and Isoform Distributions in AD and Control Subjects
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“A high frequency of acetylation occurs in the R4 region, including the sites K353, K369, K370, and K375, whereas ubiquitination occurs in R1–R3.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
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“in the insoluble fraction containing pathologic Tau, 0N and 1N Tau were enriched significantly compared with the 2N isoform, and the 4R isoform is enriched significantly compared with the 3R isoform.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Concentrations and Isoform Distributions in AD and Control Subjects
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“The Braak stage of cluster b is V, whereas the Braak stage of cluster c is VI”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“Nineteen distinct acetylation sites were mapped in BA39 and 18 in BA46.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
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“Clusters b and c display many of the same PTMs; however, in cluster c, we observe a higher frequency of several PTMs, including T175, S237, and K281 (and S113, S191, and T205, which are difficult to observe at lower stoichiometry, particularly because S113 is a phosphosite found on a 0N Tau peptide).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“These PTMs include phosphorylation occurring at adjacent sites (S262 and S263), acetylation (K311, K353, and K369), and ubiquitination (K259, K267, K311, and K317).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“These data indicate that there is an increase in the number of PTMs and the occupancy of these PTM sites observed at different stages of disease”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Stoichiometric PTM Maps of Human Pathologic Tau Identify Critical Steps in Disease Progression
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“Our analysis of pathological Tau from 91 subjects (49 AD and 42 control subjects) cumulatively identifies 95 PTMs at 88 aa residues. We mapped 55 phosphosites, 17 ubiquitination sites, 19 acetylation sites, and four methylation sites along the length of the Tau protein.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
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“The seeding-incompetent AD and control Tau sarkosyl-soluble fractions show no differences; both are enriched in the N-terminal regions (Figure 4C).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
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“Although the unmodified C-terminal peptide is found with low abundance in AD compared to all controls, there is a control cluster where the C terminus is completely unmodified (Figure 3A) and the other control cluster shows some processing.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Peptide Stoichiometry Data Identify Key Pathological Features in Disease
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“Unsupervised analyses based on the presence or absence of PTMs clustered the subjects into 4 major groups and revealed that there were specific combinations of PTMs in each of these groups.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
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“the PRR appears to accumulate phosphosites and the MBD appears to accumulate acetylation and ubiquitination with increasing size of Tau aggregates.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
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“HMW Tau, which is thought to be oligomeric Tau, displays 20 phosphosites (6 in the N terminus, 10 in the PRR, and 4 in the C-terminal region) as well as 3 acetylation and 4 ubiquitin sites in the MBD.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
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“LMW Tau shows a similar modification pattern to Tau as the sarkosyl-soluble fraction, with 6 phosphorylations (T181, S199, S202, and T231) in the PRR being consistently observed sites in LMW and sarkosyl-soluble fractions.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
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“The N-specific region is largely underrepresented (45–67, 68–87, and 88–126), as is the C terminus in AD.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Peptide Stoichiometry Data Identify Key Pathological Features in Disease
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In the paper
“Comparative analysis of the two seeding-competent fractions, HMW Tau and the larger, fibrillized, insoluble Tau, shows a similar pattern; however, the MBD is even more enriched in the insoluble Tau fraction, and the peptide 260–267 is underrepresented, indicating a higher phosphorylation stoichiometry of this peptide (S262 and T263).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
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“These sites include three KXGS motifs”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
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“Although acetylation and ubiquitination are observed in the MBD of HMW Tau”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
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“The patient frequency of these PTMs is high; however, the stoichiometry of these sites is ~50%; thus, every second Tau molecule in a fibril is modified.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, the increase in these modifications correlates positively with increasing polymer length and increased abundance of pathological Tau associated with disease progression.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“The majority of subjects in d are listed as control subjects, and these PTMs are likely to be the earliest signs of pathology.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
hedgedconditionaln = 16- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“they cannot accurately measure quantitative changes or determine PTM stoichiometry.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“suggesting that early disease is observed in a few controls.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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
“This suggests that the modification at the C terminus is an early event during aging and AD pathology and can most likely be attributed to caspase-3 and −6 cleavage at D418 and D421.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Peptide Stoichiometry Data Identify Key Pathological Features in Disease
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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
“Importantly, these data suggest that early intervention may need different therapeutic agents than late-stage AD because there are distinct differences in PTM profiles associated with each stage of disease.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“This increase in phosphorylation of Tau may be involved in neutralizing the charge in the MBD domain to promote aggregation”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Peptide Stoichiometry Data Identify Key Pathological Features in Disease
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“The sets of PTMs were largely reflective of disease progression and therefore could be associated with disease stages.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“The above results from sarkosyl-insoluble (fibrillized) Tau from AD and control subjects indicate that there is processivity and an order in which PTMs occur in the fibrillization process.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
hedgedcorrelationaln = 91- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“To ensure no bias in acquisition, samples were run in randomized order (three technical replicates per sample).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of brain tissue samples and mass spectrometry analysis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § Preparation and MS analysis of MC1-isolated Tau · plain
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
“These data suggest that the 0N and 4R version, when phosphorylated, is no longer disordered and can adopt a structure capable of fibril formation.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of brain tissue samples and mass spectrometry analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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
“All peptide transitions were evaluated for variability, similarity between y-ion ratios, elution times, and interfering signals by manual analysis.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of brain tissue samples and mass spectrometry analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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
“Peptides were considered ‘quantifiable’ if the peptide transitions had a signal-to-noise of > 3 and at least three light and three heavy high-quality SRM transitions were observed.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of brain tissue samples and mass spectrometry analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Tau contains 19 lysine residues in its microtubule-binding domain.
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
“Increased phosphorylation in the PRR results in accumulation of negative charges, which, we postulate, could neutralize the positive charge in the MBD”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Also stated in: § Preparation and MS analysis of MC1-isolated Tau · plain
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
“Randomized samples (SEC fractions 2,3,4 and 14,16,18 for 4 AD and 4 control human brain samples) were analyzed in duplicates using a Q Exactive mass spectrometer”
§ 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
plainn = 4- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Randomized samples (SEC fractions 2,3,4 and 14,16,18 for 4 AD and 4 control human brain samples) were analyzed in duplicates using a Q Exactive mass spectrometer”
§ 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
plainn = 4- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“A cutoff of 85% confidence was employed for all modified peptides.”
§ 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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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
“Peak boundaries were manually inspected and reassigned as needed to ensure correct peak detection and accurate integration.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of brain tissue samples and mass spectrometry analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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
“A cutoff of 85% confidence was employed for all modified peptides.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of brain tissue samples and mass spectrometry analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Our data support a processive model (Figure 5C) where 0N and 4R are predisposed to aggregation, cleavage of the C terminus enables fibrillization, followed by phosphorylation in the PRR domain and acetylation and ubiquitination in the MBD, which remove electrostatic repulsion of positively charged lysine residues in this region, promoting Tau fibrilization.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“Western Blot analysis using Tau13, Tau46, HT7 and DAKO antibodies confirmed that the fraction 3 and 4 are enriched for Tau (data not shown).”
§ 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“In examining the clinical records, we found that those cases with the most marked propagation potential also had the fastest clinical course and had characteristic patterns of post-translational modifications (10, 11).”
From All the Tau We Cannot See (2023) · cites this paper as [11]
In the citing paper
“For example, the microtubule-associated protein tau is often measured using antibodies that represent phosphorylation at threonine 181 and one that measures so called “total-tau”. However, at least 95 post-translational modifications have been discovered on tau with potentially many 100s of possible proteoforms resulting from the combinations.(16)”
From Putting humpty dumpty back together again: what does protein quantification mean in bottom-up proteomics? (2022) · cites this paper as [16]
In the citing paper
“Additional studies indicate that specific tau phosphosites may be better indicators of disease progression, emphasizing the importance of distinguishing between different pTau isoforms and proteoforms.(15,16)”
From Putting humpty dumpty back together again: what does protein quantification mean in bottom-up proteomics? (2022) · cites this paper as [16]
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.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
“we observe acetylation and ubiquitination as being unique to seeding-positive Tau compared with LMW and sarkosyl-soluble seeding-negative fractions.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
“Ubiquitination is unique to seeding-competent Tau, whereas acetylation is also observed in seeding-incompetent Tau.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
“These PTMs include phosphorylation occurring at adjacent sites (S262 and S263)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
“indicating a higher phosphorylation stoichiometry of this peptide (S262 and T263).”
Citations
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · cited 2×
“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.”
BackgroundMethodCox, J., & Mann, M. (2008) · Nature Biotechnology · doi:10.1038/nbt.1511 · Cited by 14,855 · cited 1×
“10 (Cox and Mann, 2008) and peptide list searched against the Homo sapiens Uniprot protein sequence database (December 2017, only reviewed entries appended with common laboratory contaminants [cRAP database, 247 entries]) using the Andromeda search engine (Cox et al.”
MethodAmyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
Universal sample preparation method for proteome analysis
Wiśniewski, J. R., Zougman, A., Nagaraj, N., & Mann, M. (2009) · Nature Methods · doi:10.1038/nmeth.1322 · Cited by 8,352
Andromeda: A Peptide Search Engine Integrated into the MaxQuant Environment
Cox, J., Neuhauser, N., Michalski, A., Scheltema, R. A., Olsen, J. V., & Mann, M. (2011) · Journal of Proteome Research · doi:10.1021/pr101065j · Cited by 5,520 · cited 1×
“10 (Cox and Mann, 2008) and peptide list searched against the Homo sapiens Uniprot protein sequence database (December 2017, only reviewed entries appended with common laboratory contaminants [cRAP database, 247 entries]) using the Andromeda search engine (Cox et al., 2011).”
MethodGlenner, G. G., & Wong, C. W. (1984) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(84)80190-4 · Cited by 5,404 · cited 1×
“Aβ forms extracellular plaques (Glenner and Wong, 1984; Masters et al., 1985), whereas Tau forms intracellular neurofibrillary tangles (NFTs) (Grundke-Iqbal et al.”
BackgroundCox, J., Hein, M. Y., Luber, C. A., Paron, I., Nagaraj, N., & Mann, M. (2014) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m113.031591 · Cited by 5,180 · cited 1×
“Label-free quantification was done using the XIC-based in-built label-free quantification (LFQ) algorithm (Cox et al., 2014) integrated into MaxQuant.”
MethodMirra, S. S., Heyman, A., McKeel, D., Sumi, S. M., Crain, B. J., Brownlee, L. M., Vogel, F. S., Hughes, J. P., Belle, G. V., Berg, L., et al. (1991) · Neurology · doi:10.1212/wnl.41.4.479 · Cited by 4,961 · cited 1×
“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.”
MethodSkyline: an open source document editor for creating and analyzing targeted proteomics experiments
MacLean, B., Tomazela, D. M., Shulman, N., Chambers, M., Finney, G. L., Frewen, B., Kern, R., Tabb, D. L., Liebler, D. C., & MacCoss, M. J. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq054 · Cited by 4,697
Amyloid plaque core protein in Alzheimer disease and Down syndrome.
Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., & Beyreuther, K. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.12.4245 · Cited by 4,431 · cited 1×
“Aβ forms extracellular plaques (Glenner and Wong, 1984; Masters et al., 1985), whereas Tau forms intracellular neurofibrillary tangles (NFTs) (Grundke-Iqbal et al.”
Background
Research works printed but not linked: 2
- Lê, 2008, FactoMineR: A Package for Multivariate Analysis, J. Stat. Softw., 25
- Lovestone, 1997, The phosphorylation of tau: a critical stage in neurodevelopment and neurodegenerative processes, Neuroscience, 78, 309
Cited by
Sorted by citations
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Hansson, O. (2021) · Nature Medicine · doi:10.1038/s41591-021-01382-x · Cited by 1,159
Blood-based biomarkers for Alzheimer's disease: towards clinical implementation
Teunissen, C. E., Verberk, I. M. W., Thijssen, E. H., Vermunt, L., Hansson, O., Zetterberg, H., van der Flier, W. M., Mielke, M. M., & del Campo, M. (2022) · The Lancet Neurology · doi:10.1016/s1474-4422(21)00361-6 · Cited by 1,045
The sirtuin family in health and disease
Wu, Q., Zhang, T., Chen, H., Yu, X., Lv, J.-L., Liu, Y., Liu, Y., Zheng, G., Zhao, J.-Q., Wei, Y., et al. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01257-8 · Cited by 928
Thijssen, E. H., La Joie, R., Strom, A., Fonseca, C., Iaccarino, L., Wolf, A., Spina, S., Allen, I. E., Cobigo, Y., Heuer, H., et al. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(21)00214-3 · Cited by 607
Self-citationApplications 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
The different autophagy degradation pathways and neurodegeneration
Fleming, A., Bourdenx, M., Fujimaki, M., Karabiyik, C., Krause, G. J., Lopez, A., Martín‐Segura, A., Puri, C., Scrivo, A., Skidmore, J., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.01.017 · Cited by 500
A current view on Tau protein phosphorylation in Alzheimer's disease
Wegmann, S., Biernat, J., & Mandelkow�, E. (2021) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2021.03.003 · Cited by 486
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Zheng, Q., & Wang, X. (2024) · Protein & Cell · doi:10.1093/procel/pwae026 · Cited by 483
Emerging diagnostics and therapeutics for Alzheimer disease
Self, W. K., & Holtzman, D. M. (2023) · Nature Medicine · doi:10.1038/s41591-023-02505-2 · Cited by 381
Alquezar, C., Arya, S., & Kao, A. W. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2020.595532 · Cited by 367
“In this regard, a study using FLEXITau has reported 95 PTMs on tau isolated from postmortem human tissue from AD and has demonstrated that these modifications occur in an ordered manner and lead to tau aggregation (310).”
BackgroundTau-targeting therapies for Alzheimer disease: Current status and future directions
Congdon, E. E., Ji, C., Tetlow, A. M., Jiang, Y., & Sigurdsson, E. M. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00883-2 · Cited by 371
Solving neurodegeneration: common mechanisms and strategies for new treatments
Wareham, L. K., Liddelow, S. A., Temple, S., Benowitz, L. I., Di Polo, A., Wellington, C., Goldberg, J. L., He, Z., Duan, X., Bu, G., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00524-0 · Cited by 324
“Other markers of neurodegeneration include Tau post-translational modification markers [204], which are suggestive of myelinated axon degeneration.”
BackgroundMass-spectrometry-based proteomics: from single cells to clinical applications
Guo, T., Steen, J. A. J., & Mann, M. (2025) · Nature · doi:10.1038/s41586-025-08584-0 · Cited by 362
“For instance, studies have uncovered the processive nature of ubiquitination and phosphorylation during key cellular processes such as cell-cycle progression, signal transduction and ageing-associated degeneration 79 .”
Self-citationBiomarker modeling of Alzheimer’s disease using PET-based Braak staging
Therriault, J., Pascoal, T. A., Lussier, F. Z., Tissot, C., Chamoun, M., Bezgin, G., Servaes, S., Benedet, A. L., Ashton, N. J., Karikari, T. K., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00204-0 · Cited by 308
“Furthermore, the histopathological Braak staging framework is based on staining procedures that preferentially identify specific tau phosphorylation sites 44 ; the degree to which these phosphorylation sites contribute to tau-PET ligand binding signal is unknown.”
Lövestam, S., Koh, F. A., van Knippenberg, B., Kotecha, A., Murzin, A. G., Goedert, M., & Scheres, S. H. W. (2022) · eLife · doi:10.7554/elife.76494 · Cited by 306
Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids
Scheres, S. H. W., Falcon, B., & Goedert, M. (2023) · Nature · doi:10.1038/s41586-023-06437-2 · Cited by 308
Emerging roles of innate and adaptive immunity in Alzheimer’s disease
Chen, X., & Holtzman, D. M. (2022) · Immunity · doi:10.1016/j.immuni.2022.10.016 · Cited by 297
Proteomic landscape of Alzheimer’s Disease: novel insights into pathogenesis and biomarker discovery
Bai, B., Vanderwall, D., Li, Y., Wang, X., Poudel, S., Wang, H., Dey, K. K., Chen, P., Yang, K., & Peng, J. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00474-z · Cited by 267
Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease
Rajesh, Y., & Kanneganti, T. (2022) · Cells · doi:10.3390/cells11121885 · Cited by 269
“Normally, Tau binds microtubules to stabilize them, impacting synaptic functions [10].”
BackgroundMechanisms and pathology of protein misfolding and aggregation
Louros, N. N., Schymkowitz, J. W. H., & Rousseau, F. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00647-2 · Cited by 271
“Transcriptomics and proteomics have enabled characterization of amyloid species in complex biological matrices, enabling the study of the diversity and specificity of amyloid formation 14–16 .”
BackgroundMolecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease
Otero-Garcia, M., Mahajani, S. U., Wakhloo, D., Tang, W., Xue, Y.-Q., Morabito, S., Pan, J., Oberhauser, J., Madira, A. E., Shakouri, T., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.06.021 · Cited by 262
Cellular and pathological functions of tau
Bravo, C. P., Naguib, S. A., & Gan, L. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00753-9 · Cited by 271
“especially in the PRR and MTBR domains 58,79 (Fig.”
Xia, Y., Prokop, S., & Giasson, B. I. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00460-5 · Cited by 227
“A recent quantitative mass spectrometry study examined a cohort of 49 AD patients and 42 AD control subjects and greatly expanded the number of potential phosphorylation sites found in AD and control brains [5].”
BackgroundReducing acetylated tau is neuroprotective in brain injury
Shin, M.-K., Vázquez-Rosa, E., Koh, Y., Dhar, M., Chaubey, K., Cintrón-Pérez, C. J., Barker, S., Miller, E., Franke, K., Noterman, M. F., et al. (2021) · Cell · doi:10.1016/j.cell.2021.03.032 · Cited by 226
Mouse Models of Alzheimer’s Disease
Yokoyama, M., Kobayashi, H., Tatsumi, L., & Tomita, T. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.912995 · Cited by 213
Bayoumy, S., Verberk, I. M. W., den Dulk, B., Hussainali, Z., Zwan, M. D., van der Flier, W. M., Ashton, N. J., Zetterberg, H., Blennow, K., Vanbrabant, J., et al. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-021-00939-9 · Cited by 196
“Some post-translational modifications were reported to occur at earlier stages of the AD disease process in the brain tissue [29].”
BackgroundSafety and Efficacy of Semorinemab in Individuals With Prodromal to Mild Alzheimer Disease
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Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607
Shi, Y., Murzin, A. G., Falcon, B., Epstein, A., Machin, J., Tempest, P. A., Newell, K. L., Vidal, R., Garringer, H. J., Sahara, N., et al. (2021) · Acta Neuropathologica · doi:10.1007/s00401-021-02294-3 · Cited by 189
Updates in Alzheimer's disease: from basic research to diagnosis and therapies
Liu, E., Zhang, Y., & Wang, J. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00432-x · Cited by 241
Limorenko, G., & Lashuel, H. A. (2021) · Chemical Society Reviews · doi:10.1039/d1cs00127b · Cited by 168
More than a marker: potential pathogenic functions of MAP2
DeGiosio, R. A., Grubisha, M. J., MacDonald, M. L., McKinney, B. C., Camacho, C. J., & Sweet, R. A. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.974890 · Cited by 173
Roberts, D. S., Loo, J. A., Tsybin, Y. O., Liu, X., Wu, S., Chamot-Rooke, J., Agar, J. N., Paša-Tolić, L., Smith, L. M., & Ge, Y. (2024) · Nature Reviews Methods Primers · doi:10.1038/s43586-024-00318-2 · Cited by 161
Neurodegenerative Disease Tauopathies
Creekmore, B. C., Watanabe, R., & Lee, E. B. (2023) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-051222-120750 · Cited by 155
X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women
Yan, Y., Wang, X., Chaput, D., Shin, M.-K., Koh, Y., Gan, L., Pieper, A. A., Woo, J.-A. A., & Kang, D. E. (2022) · Cell · doi:10.1016/j.cell.2022.09.002 · Cited by 144
Buchholz, S., & Zempel, H. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13784 · Cited by 154
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BackgroundLeuzy, A., Janelidze, S., Mattsson-Carlgren, N., Palmqvist, S., Jacobs, D., Cicognola, C., Stomrud, E., Vanmechelen, E., Dage, J. L., & Hansson, O. (2021) · Neurology · doi:10.1212/wnl.0000000000012727 · Cited by 128
“Recent mass spectrometry–based work(44) addressing tau PTMs has shown that p-tau181, p-tau217, and p-tau231 appear to be indicators of early AD pathology based on Braak NFT staging of postmortem brain tissue.(18) In a related study exploring the biochemical link between measures of Aβ and tau phosphorylation, however,…”
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Li, D., & Liu, C. (2022) · Nature reviews. Neuroscience · doi:10.1038/s41583-022-00603-7 · Cited by 124
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Ebert, T., Ngoc, T. U., Schurgers, L. J., Stenvinkel, P., & Shiels, P. G. (2022) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2022.101099 · Cited by 122
Disease-Modifying Therapies for Alzheimer’s Disease: More Questions than Answers
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BackgroundInfluentialDisease staging of Alzheimer’s disease using a CSF-based biomarker model
Salvadó, G., Horie, K., Barthélemy, N. R., Vogel, J. W., Binette, A. P., Chen, C. D., Aschenbrenner, A. J., Gordon, B. A., Benzinger, T. L. S., Holtzman, D. M., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00599-y · Cited by 129
“Previous studies already suggested that changes in the levels of tau fragments phosphorylated at different sites may be linked mechanistically and could be associated with disease stages 47–51 .”
BackgroundTau interactome and RNA binding proteins in neurodegenerative diseases
Kavanagh, T., Halder, A., & Drummond, E. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00572-6 · Cited by 111
“Recent mass spectrometry studies have identified numerous additional phosphorylation sites on tau, and further characterised tau’s less abundant PTMs including acetylation, methylation, and ubiquitination [58, 113].”
BackgroundCondensed-phase signaling can expand kinase specificity and respond to macromolecular crowding
Sang, D., Shu, T., Pantoja, C. F., de Opakua, A. I., Zweckstetter, M., & Holt, L. J. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.08.016 · Cited by 96
“Multiple kinases have been reported to phosphorylate Tau (Wesseling et al., 2020), including the CDK2/ Cyclin A1 complex (CDK2/CycA1) (Lee et al., 2017).”
High-throughput cryo-EM structure determination of amyloids
Lövestam, S., & Scheres, S. H. W. (2022) · Faraday Discussions · doi:10.1039/d2fd00034b · Cited by 92
Noori, A., Mezlini, A. M., Hyman, B. T., Serrano-Pozo, A., & Das, S. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105225 · Cited by 98
“, lack of a stable tertiary structure), which would render them prone to misfolding and subsequent aggregation in pathological conditions (Jarosz and Khurana, 2017), for example upon certain abnormal post-translational modifications (Toth-Petroczy et al., 2016; Wesseling et al., 2020).”
Self-citationZola, N. K. N., Balty, C., Ruys, S. P. D., Vanparys, A., Huyghe, N. D., Herinckx, G., Johanns, M., Boyer, E., Kienlen‐Campard, P., Rider, M. H., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39328-1 · Cited by 103
Classification of diseases with accumulation of Tau protein
Kovács, G. G., Ghetti, B. F., & Goedert, M. (2022) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12792 · Cited by 93
Plubell, D. L., Käll, L., Webb-Robertson, B.-J., Bramer, L. M., Ives, A., Kelleher, N. L., Smith, L. M., Montine, T. J., Wu, C. C., & MacCoss, M. J. (2022) · Journal of Proteome Research · doi:10.1021/acs.jproteome.1c00894 · Cited by 85
Cellular senescence of renal tubular epithelial cells in acute kidney injury
Chen, J., Zhang, H., Yi, X., Dou, Q., Yang, X., Chen, J., Chen, J., & Chen, K. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-01831-9 · Cited by 103
Liquid–liquid phase separation of Tau by self and complex coacervation
Najafi, S., Lin, Y., Longhini, A. P., Zhang, X., Delaney, K. T., Kosik, K. S., Fredrickson, G. H., Shea, J., & Han, S. (2021) · Protein Science · doi:10.1002/pro.4101 · Cited by 90
“2,15–19 Tau is subject to intensive post-translation modifications (PTMs) including hyperphosphorylation, acetylation, ubiquitination, and sumoylation which have been found to be correlated with, or protective of, AD disease progression.(20,21) The non-polar residues of Tau such as leucine, valine and tyrosine, due to…”
BackgroundSelf-citationO-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology
Balana, A. T., Mahul-Mellier, A.-L., Nguyen, B. A., Horvath, M., Javed, A., Hard, E. R., Jasiqi, Y., Singh, P., Afrin, S., Pedretti, R., et al. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01551-2 · Cited by 84
Microtubule-binding core of the tau protein
Mammeri, N. E., Dregni, A. J., Duan, P., Wang, H. K., & Hong, M. (2022) · Science Advances · doi:10.1126/sciadv.abo4459 · Cited by 88
“R′ contains many disease-relevant posttranslational modifications such as T386 and S396 phosphorylation, K369 and K385 ubiquitination, and Lys acetylation ( 36 ).”
Kuzu, O. F., Granerud, L. J. T., & Saatcioglu, F. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02439-w · Cited by 128
Moore, K. B. E., Hung, T.-J., & Fortin, J. S. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103487 · Cited by 93
Plasma p‐tau immunoassays in clinical research for Alzheimer's disease
Teunissen, C. E., Kolster, R., Triana‐Baltzer, G., Janelidze, S., Zetterberg, H., & Kolb, H. C. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14397 · Cited by 96
“57 Consistentwiththeabovestudy,anotherMSstudy 72 demonstrated that p-tau217 and p-tau262 were among the most relevant phosphorylation sites in distinguishing AD from control brain tissue, showing performance superior to p-tau181.”
Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses
Meng, J. X., Zhang, Y., Saman, D., Haider, A. M., De, S., Sang, J. C., Brown, K., Jiang, K., Humphrey, J., Julian, L., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30461-x · Cited by 84
Epigenetics in Alzheimer’s Disease
Gao, X., Chen, Q., Yao, H., Tan, J., Liu, Z., Zhou, Y., & Zou, Z. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.911635 · Cited by 89
The Use of Tau PET to Stage Alzheimer Disease According to the Braak Staging Framework
Macedo, A. C., Tissot, C., Therriault, J., Servaes, S., Wang, Y.-T., Arias, J. F., Rahmouni, N., Lussier, F. Z., Vermeiren, M. R., Bezgin, G., et al. (2023) · Journal of Nuclear Medicine · doi:10.2967/jnumed.122.265200 · Cited by 99
“First, Braak histopathologic staging relies on the use of staining techniques to detect specific tau phosphorylation sites (49), but the extent of their contribution to the tau PET signal is yet to be clarified.”
BackgroundStructure of Tau filaments in Prion protein amyloidoses
Hallinan, G. I., Hoq, M. R., Ghosh, M., Vago, F. S., Fernández, A., Garringer, H. J., Vidal, R., Jiang, W., & Ghetti, B. F. (2021) · Acta Neuropathologica · doi:10.1007/s00401-021-02336-w · Cited by 77
Brotzakis, Z. F., Lindstedt, P. R., Taylor, R. J., Rinauro, D. J., Gallagher, N. C. T., Bernardes, G. J. L., & Vendruscolo, M. (2021) · ACS Central Science · doi:10.1021/acscentsci.1c00585 · Cited by 70
Significance of Programmed Cell Death Pathways in Neurodegenerative Diseases
Guo, D., Liu, Z., Zhou, J., Ke, C., & Li, D. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25189947 · Cited by 83
“Meanwhile, type 2 microtubule-associated protein (Tau) is expressed in neurons, astrocytes, and oligodendrocytes and is responsible for stabilizing microtubule structures by directly binding to them [211].”
BackgroundLashuel, H. A. (2021) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2021.05.006 · Cited by 74
“A recent comprehensive analysis of Tau PTMs in post mortem brains from 49 AD and 42 healthy individuals identified 95 PTMs on 88 amino acids in human Tau, including 55, 17, 19, and 4 phosphorylation, ubiquitination, acetylation, and methylation sites in sarcosyl-insoluble Tau [31].”
BackgroundUltrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43
Tarutani, A., Adachi, T., Akatsu, H., Hashizume, Y., Hasegawa, K., Saito, Y., Robinson, A., Mann, D. M. A., Yoshida, M., Murayama, S., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02426-3 · Cited by 74
“The profiles of these PTMs in AD cases have been shown to change depending on the Braak stage [306].”
BackgroundInfluentialFluent molecular mixing of Tau isoforms in Alzheimer’s disease neurofibrillary tangles
Dregni, A. J., Duan, P., Xu, H. W., Changolkar, L. N., Mammeri, N. E., Lee, V. M. ‐., & Hong, M. (2022) · Nature Communications · doi:10.1038/s41467-022-30585-0 · Cited by 76
Peet, B. T., Spina, S., Mundada, N., & La Joie, R. (2021) · Neurotherapeutics · doi:10.1007/s13311-021-01101-x · Cited by 74
Patel, H., Martínez, P., Perkins, A., Taylor, X., Jury, N., McKinzie, D. L., & Lasagna‐Reeves, C. A. (2021) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2021.09.006 · Cited by 58
“…the PS19 mouse model, the levels of soluble tau species phosphorylated at Serine 214, an early event of phosphorylation ( Augustinack et al., 2002 ; Wesseling et al., 2020 ), and phosphorylated at Threonine 217, a recently identified potent blood biomarker ( Janelidze et al., 2020 ), correlate…”
BackgroundZhang, D., Zhang, W., Chen, M., Gao, X., Yuan, H., Lin, X., Mao, X., Wang, C., Guo, X., Du, Y., et al. (2024) · Neuron · doi:10.1016/j.neuron.2024.02.017 · Cited by 75
Moloney, C. M., Labuzan, S. A., Crook, J. E., Siddiqui, H., Castanedes‐Casey, M., Lachner, C., Petersen, R. C., Duara, R., Graff‐Radford, N. R., Dickson, D. W., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12749 · Cited by 76
Phage display derived peptides for Alzheimer's disease therapy and diagnosis
Zhang, X., Zhang, X., Gao, H., & Qing, G. (2022) · Theranostics · doi:10.7150/thno.68636 · Cited by 75
“This includes the widely known phosphorylation modification, as well as glycosylation, acetylation, methylation and ubiquitination [87, 88].”
BackgroundIslam, T., Hill, E., Abrahamson, E. E., Servaes, S., Smirnov, D. S., Zeng, X., Sehrawat, A., Chen, Y., Kac, P. R., Kvartsberg, H., et al. (2025) · Nature Medicine · doi:10.1038/s41591-024-03400-0 · Cited by 76
Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures
Hu, J., Xia, W., Zeng, S., Lim, Y., Tao, Y., Sun, Y., Zhao, L., Wang, H., Le, W., Li, D., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46898-1 · Cited by 66
“Instead, the N-terminal half (1-72) shapes a novel arch-like fibril structure.”
The necroptosis cell death pathway drives neurodegeneration in Alzheimer’s disease
Balusu, S., & Strooper, B. D. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02747-5 · Cited by 76
“Polyubiquitination could indeed contribute to Tau accumulation within GVDs, particularly in the presence of autophagy defects [31, 33, 171].”
BackgroundCellular localization of p-tau217 in brain and its association with p-tau217 plasma levels
Wennström, M., Janelidze, S., Nilsson, K. P. R., Bank, T. N. B., Serrano, G. E., Beach, T. G., Dage, J. L., & Hansson, O. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01307-2 · Cited by 59
“Importantly, phosphorylation of tau can occur at several different sites and give rise to different p-tau variants [5, 25].”
BackgroundStathas, S., Alvarez, V. E., Xia, W., Nicks, R., Meng, G., Daley, S. A., Pothast, M. J., Shah, A., Kelley, H. J., Esnault, C. D., et al. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12502 · Cited by 62
Targeting tau in Alzheimer's disease: from mechanisms to clinical therapy
Ye, J., Wan, H., Chen, S., & Liu, G. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.385847 · Cited by 74
“Specifically, a recent study that analyzed the PTM profile of tau found that these PTMs occur in a processive fashion, reflecting AD progression (Wesseling et al., 2020). on the recognized motif in the tau sequence: proline-directed protein kinases, tyrosine protein kinases, and…”
Tau and Membranes: Interactions That Promote Folding and Condensation
Sallaberry, C. A., Voss, B. J., Majewski, J. P., Biernat, J., Mandelkow�, E., Chi, E. Y., & Zanden, C. M. V. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.725241 · Cited by 64
Ferroptosis, Pyroptosis, and Cuproptosis in Alzheimer’s Disease
Wang, Q., Sun, J., Chen, T., Song, S., Hou, Y., Feng, L., Fan, C., & Li, M. (2023) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.3c00343 · Cited by 65
The Enigma of Tau Protein Aggregation: Mechanistic Insights and Future Challenges
Zheng, H., Sun, H., Cai, Q., & Tai, H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094969 · Cited by 69
“Four of them target hyperphosphorylation sites (pT212/pT217, pT231, or pS396/pS404) associated with AD-PHF tau, but these sites are also phosphorylated in non-demented elderly [94].”
BackgroundBiofluid Biomarkers of Alzheimer’s Disease: Progress, Problems, and Perspectives
Huang, S., Wang, Y., & Guo, J. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-022-00836-7 · Cited by 63
Tau Toxicity in Neurodegeneration
Liang, S., Wang, Z.-T., Tan, L., & Yu, J. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02809-3 · Cited by 61
“However, a recent study showed that tau misfolding occurred earlier than tau phosphorylation [26].”
BackgroundGuen, Y. L., Luo, G., Ambati, A., Damotte, V., Jansen, I. E., Yu, E., Nicolas, A., de Rojas, I., Leal, T. P., Miyashita, A., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2302720120 · Cited by 63
“K311 is not only acetylated, but also methylated, ubiquitinated (32, 55), or succinylated (56), and the epitope is trafficked to the NLRP3 inflammasome of microglial cells (57), where HLA class II presentation of tau fragments by HLA-DRB1 *04 to T cells is also likely to occur (58).”
Quantitative phosphoproteomics uncovers dysregulated kinase networks in Alzheimer’s disease
Morshed, N., Lee, M. J., Rodriguez, F. H., Lauffenburger, D. A., Mastroeni, D., & White, F. M. (2021) · Nature Aging · doi:10.1038/s43587-021-00071-1 · Cited by 58
Liu, Q., Wang, X., Hu, Y., Zhao, J.-N., Huang, C.-H., Li, T., Zhang, B.-G., He, Y., Wu, Y.-Q., Zhang, Z.-J., et al. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102697 · Cited by 58
Stress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate
Carrettiero, D. C., Almeida, M. C., Longhini, A. P., Rauch, J. N., Han, D., Zhang, X., Najafi, S., Gestwicki, J. E., & Kosik, K. S. (2022) · Nature Communications · doi:10.1038/s41467-022-30751-4 · Cited by 52
Self-citationHsp multichaperone complex buffers pathologically modified Tau
Moll, A., Ramirez, L. M., Ninov, M., Schwarz, J., Urlaub, H., & Zweckstetter, M. (2022) · Nature Communications · doi:10.1038/s41467-022-31396-z · Cited by 60
Clinical value of plasma ALZpath pTau217 immunoassay for assessing mild cognitive impairment
Lehmann, S., Schraen‐Maschke, S., Vidal, J., Delaby, C., Buée, L., Blanc, F., Paquet, C., Allinquant, B., Bombois, S., Gabelle, A., et al. (2024) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2024-333467 · Cited by 62
Common mouse models of tauopathy reflect early but not late human disease
Wenger, K., Viodé, A., Schlaffner, C. N., van Zalm, P., Cheng, L., Dellovade, T., Langlois, X., Bannon, A. W., Chang, R., Connors, T. R., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00601-y · Cited by 55
“identified at different disease stages of human AD [20], the P301S and the”
BackgroundMethodResultInfluentialSelf-citationDistinct populations of highly potent TAU seed conformers in rapidly progressing Alzheimer’s disease
Kim, C., Haldiman, T., Kang, S.-G., Hromadkova, L., Han, Z. Z., Chen, W., Lissemore, F., Lerner, A., de Silva, R., Cohen, M. L., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abg0253 · Cited by 55
Murray, M. E., Moloney, C. M., Kouri, N., Syrjanen, J. A., Matchett, B. J., Rothberg, D. M., Tranovich, J. F., Sirmans, T. N. H., Wiste, H. J., Boon, B. D. C., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00578-0 · Cited by 58
“A high-resolution quantitative proteomics study of tau demonstrated that phosphorylation at threonine 181 was observed in 70% of clinical controls with a Braak stage <IV and 92% of AD cases [69].”
BackgroundAinani, H., Bouchmaa, N., Ben Mrid, R., & El Fatimy, R. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106011 · Cited by 54
Chemical Features of Polyanions Modulate Tau Aggregation and Conformational States
Montgomery, K. M., Carroll, E. C., Thwin, A. C., Quddus, A., Hodges, P., Southworth, D. R., & Gestwicki, J. E. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c08004 · Cited by 48
Saurat, N. G., Minotti, A. P., Rahman, M. T., Sikder, T., Zhang, C., Cornacchia, D., Jungverdorben, J., Ciceri, G., Betel, D., & Studer, L. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.06.001 · Cited by 60
A multifactorial model of pathology for age of onset heterogeneity in familial Alzheimer’s disease
Sepulveda-Falla, D., Chavez-Gutierrez, L., Portelius, E., Vélez, J. I., Dujardin, S., Barrera-Ocampo, A., Dinkel, F., Hagel, C., Puig, B., Mastronardi, C., et al. (2021) · Acta Neuropathologica · doi:10.1007/s00401-020-02249-0 · Cited by 54
Self-citationTau Ubiquitination in Alzheimer's Disease
Li, L., Jiang, Y., Wang, J., Liu, R., & Wang, X. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2021.786353 · Cited by 57
Dregni, A. J., Wang, H. K., Wu, H., Duan, P., Jin, J., DeGrado, W. F., & Hong, M. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c03314 · Cited by 50
Omics-based biomarkers discovery for Alzheimer's disease
Aerqin, Q., Wang, Z.-T., Wu, K., He, X., Dong, Q., & Yu, J. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04614-6 · Cited by 56
“, so as to identify the proteins and biological processes that play roles in AD [11].”
BackgroundAdvances in treatment of frontotemporal dementia
Magrath Guimet, N., Zapata-Restrepo, L. M., & Miller, B. L. (2022) · The Journal of Neuropsychiatry and Clinical Neurosciences · doi:10.1176/appi.neuropsych.21060166 · Cited by 52
Self-citationHow do protein aggregates escape quality control in neurodegeneration?
Koopman, M. B., Ferrari, L., & Rüdiger, S. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2022.01.006 · Cited by 54
Xu, T., Wang, Q., Wang, Q., & Sun, L. (2024) · Analytical Methods · doi:10.1039/d4ay00651h · Cited by 54
Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau
de Gérando, A. M., Welikovitch, L. A., Khasnavis, A., Commins, C., Glynn, C. A., Chun, J. E., Perbet, R., & Hyman, B. T. (2023) · Acta Neuropathologica · doi:10.1007/s00401-023-02600-1 · Cited by 54
“Post-translational modification differences between SARK and HMW tau as reported recently [60] may also account for differential trafficking between these two tau species.”
BackgroundResultSelf-citation
Metadata
- 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)
- 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
- 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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