The DOI matches its Crossref record; 20 of the 20 references it cites were found in a registry or an index; 10 of the 24 sources its claims cite were checked for support.
Glycogen synthase kinase-3β phosphorylates tau protein at multiple sites in intact cells
Open accessAbstract
Hyperphosphorylated tau protein is the major constituent of the paired helical filament (PHF), the major fibrous component of the neurofibrillary lesions of Alzheimer's disease (AD). Hyperphosphorylation of tau is believed to be the critical event that leads to filament assembly. Identification of the responsible protein kinases is therefore a key step towards an understanding of the pathogenesis of AD. Mitogen-activated protein kinase, glycogen synthase kinase-3 (GSK3) and neuronal cdc2-like kinase have been shown to phosphorylate tau protein in vitro at a number of sites that are phosphorylated in PHFs. In this study, we report that transient transfection of human GSK3 beta into Chinese hamster ovary cells stably transfected with individual human tau isoforms leads to hyperphosphorylation of tau at all the sites investigated with phosphorylation-dependent anti-tau antibodies. Thus, GSK3 beta is a protein kinase that phosphorylates tau protein in intact cells.
Overview
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Written from the paper’s full text.
TL;DR
Transient expression of a constitutively active human GSK3β mutant in CHO cells stably expressing human tau increased tau phosphorylation at multiple PHF-associated sites. This extends in vitro evidence that GSK3β can phosphorylate tau to an intact-cell system.
Key findings
- Transfection of GSK3β(S9A) into CHO T40 and CHO T44 tau-expressing cells increased immunoreactivity with all phosphorylation-dependent anti-tau antibodies tested: PHF1 (Ser-396/Ser-404), T3P (Ser-396), AT270 (Thr-181), AT180 (Thr-231), and AT8 (Ser-202).
- GSK3β expression also caused a decrease in electrophoretic mobility of tau consistent with phosphorylation, while total tau amount remained unchanged by immunoblot.
- GSK3β was distributed throughout the cytoplasm and was not exclusively microtubule-associated; the c-myc-tagged protein ran at approximately 48 kDa in transfected cells.
- Attempts to make cell lines stably expressing both GSK3β and tau were unsuccessful because CHO cells did not survive high sustained GSK3β activity.
Methods
- Human GSK3β was mutated at Ser-9 to Ala to produce a constitutively active enzyme, tagged with c-myc, and subcloned into pSG5.
- The construct was transiently transfected by DEAE/dextran into CHO cells stably expressing three-repeat tau (CHO T44) or two N-terminal insert four-repeat tau (CHO T40); >95% of these cells expressed tau, while about 2–10% expressed high GSK3β levels.
- Tau phosphorylation was assessed 48 h after transfection by indirect immunofluorescence and immunoblotting with phosphorylation-dependent and phosphorylation-independent anti-tau antibodies.
Limitations
- The paper states that the model system does not represent physiological conditions and that only a subset of tau transfectants expressed GSK3β, making increased tau phosphorylation modest and difficult to quantify across transient transfections.
- The paper notes that GSK3β might have activated other kinases or inhibited phosphatases, although prior in vitro data support direct phosphorylation at many observed sites.
- Evident from the text: the study uses overexpression of a constitutively active GSK3β mutant in CHO cells rather than endogenous GSK3β, and the antibody panel samples only a limited set of phosphorylation sites.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
7 Own interpretation · 6 Own result · 4 Own method · 2 Supported so far · 2 Partly supported · 2 No full text of the sources · 1 Supported · 1 Couldn’t confirm · 1 Sources not found · 1 No basis given · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, without exception, these studies have been carried out in vitro.”
§ NEUROSCI ENCE > Abstract
What the sources say
- Could not verifycites [2] Drewes, 1992, Mitogen activated protein (MAP) kinase transform tau protein into an Alzheimer-like state, EMBO J. sourceExperimental — accuracy not yet measured
The indexed copy’s Full text section lists PDF page images rather than readable passages from the paper’s body. Searches for in vitro and in vivo tau phosphorylation found no passage stating that all prior studies of phosphorylation by these kinases were conducted in vitro; the reference list cannot establish the 'without exception' claim. (LLM, conf=0.75)
- Partly supportedcites [4] Goedert, 1992, p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1, FEBS Lett. sourceExperimental — accuracy not yet measured
The Introduction describes prior work in which a kinase purified from pig brain phosphorylated recombinant tau, and Methods §2.2 describes this paper’s phosphorylation assay using isolated tau and kinase. These passages support an in-vitro characterization, but the paper does not establish that every prior study of tau phosphorylation by the kinases was conducted in vitro. The indexed copy provides section labels but no page numbers for these passages. (LLM, conf=0.82)
- Not checked — no full text of the sourcecites [7] Hanger, 1992, Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localization of the kinase, Neurosci. Lett. source
- Partly supportedcites [12] Mandelkow, 1992, Glycogen synthase kinase 3 and the Alzheimer's disease-like state of microtubule-associated protein tau, FEBS Lett. sourceExperimental — accuracy not yet measured
The discussion (p. 56) says tau phosphorylation by several common kinases has been studied in vitro and that whether those modifications occur in vivo remains uncertain. It does not establish the stronger claim that every study of tau phosphorylation by the kinases in question was carried out in vitro. (LLM, conf=0.82)
- Not checked — no full text of the sourcecites [14] Paudel, 1993, Brain prolinedirected protein kinase phosphorylates tau on sites that are abnormally phosphorylated in tau associated with Alzheimer's paired helical filaments, J. Biol. Chem. source
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.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Mitogen-activated protein kinase, glycogen synthase kinase-3 (GSK3) and neuronal cdc2-1ike kinase have been shown to phosphorylate tau protein in vitro at a number of sites that are phosphorylated in PHFs.”
- Also stated in: § Abstract · plain
“These include mitogen-activated protein (MAP) kinase, glycogen synthase kinase-3 (GSK3) and neuronal cdc2-1ike kinase (or cdk5) [2,4,7,12,14].”
§ NEUROSCI ENCE > Abstract
What the sources say
- Partly supportedcites [2] Drewes, 1992, Mitogen activated protein (MAP) kinase transform tau protein into an Alzheimer-like state, EMBO J. sourceExperimental — accuracy not yet measured
The passage labeled Abstract in our indexed copy reports that MAP kinase phosphorylates tau and induces an Alzheimer-like state. It does not establish the claim for GSK3 or neuronal cdc2-like kinase (cdk5), and the passages retrieved for those terms provide no such result. The copy instead says that p34(cdc2) with cyclin A or B has only minor effects on tau phosphorylation; it does not identify p34(cdc2) as cdk5. (LLM, conf=0.85)
- Partly supportedcites [4] Goedert, 1992, p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1, FEBS Lett. sourceExperimental — accuracy not yet measured
The Discussion reports that p42 MAP kinase phosphorylates tau at sites abnormally phosphorylated in PHF tau. The Introduction also mentions other tau-phosphorylating kinases, but our copy does not identify them as GSK3 or neuronal cdc2-like kinase or establish the claimed result for those two enzymes. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [7] Hanger, 1992, Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localization of the kinase, Neurosci. Lett. source
- Partly supportedcites [12] Mandelkow, 1992, Glycogen synthase kinase 3 and the Alzheimer's disease-like state of microtubule-associated protein tau, FEBS Lett. sourceExperimental — accuracy not yet measured
The Introduction and section 3.1 support in-vitro phosphorylation of tau by MAP kinase and GSK3 and describe Alzheimer-like phosphorylation. They do not establish the claim for neuronal cdc2-like kinase (cdk5): the Introduction instead discusses cell-cycle cdc2, reporting only slight phosphorylation and no Alzheimer-like immune response. Page numbers are unavailable in our copy. (LLM, conf=0.89)
- Not checked — no full text of the sourcecites [14] Paudel, 1993, Brain prolinedirected protein kinase phosphorylates tau on sites that are abnormally phosphorylated in tau associated with Alzheimer's paired helical filaments, J. Biol. Chem. source
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.
- Also stated in: § Abstract · plain
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
“Using PHF1 and antibody 9El0 in double immunofluorescence studies, we observed a significant increase in PHF1 immunoreactivity in cells expressing the GSK3fl construct (Fig. 2E,F).”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
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.
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
“By indirect immunofluorescence using the c-myc MAb, GSK3fl was distributed throughout the cytoplasm of CHO cells which expressed the construct (Fig. 2A).”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
plain- 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.
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
“In this study, we report that transient transfection of human GSK3fl into Chinese hamster ovary cells stably transfected with individual human tau isoforms leads to hyperphosphorylation of tau at all the sites investigated with phosphorylation-dependent anti-tau antibodies.”
- Also stated in: § GSK3I]S9Amyc: · plain
“However, transient transfection of CHO T40 and CHO T44 cells with GSK3fl resulted in increased immunoreactivity with all the phosphorylation-dependent anti-tau antibodies investigated.”
§ NEUROSCI ENCE > Abstract
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.
- Also stated in: § GSK3I]S9Amyc: · 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
“However, all cells that expressed GSK3fl also showed increased PHF1 staining, indicating that Ser-396 and Ser- 404 were phosphorylated by GSK3fl.”
- Also stated in: § GSK3I]S9Amyc: · hedged
“The increased phosphorylation of Ser-396 and Ser-404 in CHO T40 and CHO T44 ceils expressing GSK3fl could also be demonstrated by immunoblot analysis.”
- Also stated in: § GSK3I]S9Amyc: · boosted
“Thus, we demonstrate by both sequential immunofluorescence and immunobiotting that overexpression of GSK3fl causes increased tau phosphorylation at Ser-396 and Ser-404.”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
boosteddirect- 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.
- Also stated in: § GSK3I]S9Amyc: · hedged
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
“Controls included omitting either the first or second primary antibody, but using both secondary antibodies.Results from these controls showed no cross-over of staining in the channels for Texas Red or FITC.”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
plain- 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.
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
“Because GSK3fl is only expressed in a fraction of the tau transfectants (about 2-10%), increased tau phosphorylation occurs only in those cells that express both GSK3fl and tau protein (Fig. 2E-L).”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
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.
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
“The amount of tau protein in GSK3fl-expressing and mock-transfected CHO T40 and CHO T44 cells remained unchanged (Fig. 3B).”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
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.
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
“Since parallel studies with T14/46 showed no increased in immunoreactivity in cells expressing GSK3fl (Fig. 2C,D), significant crossover was unlikely in the double label experiments described above.”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
hedged- 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. 6
- Probably not a substantial claim. 6
- The quote only partly states this claim. 2
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“They extend results obtained in vitro [7,12,14] to an in vivo model system, and indicate that GSK3fl may be involved in the phosphorylation of tau in vivo.”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
What the sources say
- Not checked — no full text of the sourcecites [7] Hanger, 1992, Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localization of the kinase, Neurosci. Lett. source
- Supportedcites [12] Mandelkow, 1992, Glycogen synthase kinase 3 and the Alzheimer's disease-like state of microtubule-associated protein tau, FEBS Lett. source
The citation is attached to “results obtained in vitro,” not to the citing authors’ extension to an in vivo model. The Results (section 3.1) report that GSK3 phosphorylated tau and altered its antibody response and electrophoretic mobility, supporting the attributed in vitro finding. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [14] Paudel, 1993, Brain prolinedirected protein kinase phosphorylates tau on sites that are abnormally phosphorylated in tau associated with Alzheimer's paired helical filaments, J. Biol. Chem. source
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.
- Rests on an assumption: Findings in GSK3β-transfected CHO cells are relevant to GSK3β-mediated tau phosphorylation in vivo.
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Thus, phosphorylation of GSK3fl by MAP kinaseactivated protein kinase-1 and p70 $6 kinase at Ser 9 decreases its activity by 95% [17].”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
What the sources say
- Could not verifycites [17] Sutherland, 1993, Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signaling, Biochem. J. sourceExperimental — accuracy not yet measured
The indexed copy gives the 90–95% inactivation, the two kinases, and Ser-9 only in its Abstract, which cannot serve as evidence under this rubric. Searches for the activity reduction and Ser-9 found no Results or other body-text passage; the apparent full-text section contains links rather than the article text. (LLM, conf=0.70)
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.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“By immunoblotting the c-myc MAb recognized a band with an apparent molecular mass of ap- proximately 48 kDa only in transfected CHO cells (Fig. 3A), consistent with the apparent molecular mass of recombinant GSK3fl [ 19] with an added c-myc tail.”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
What the sources say
- Supportedcites [19] Woodgett, 1990, Molecular cloning and expression of glycogen synthase kinase-3/factor A, EMBO J. source
In “Expression of GSK-3 cDNAs,” the source reports a 47 kDa protein in cells transfected with GSK-3β DNA. The citation is attached to the comparison with the apparent mass of recombinant GSK-3β, not to the citing paper’s observation of a c-myc-reactive band in CHO cells. (LLM, conf=0.90)
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.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“However, since in vitro studies [7,12,14] have demonstrated that tau can be directly phosphorylated by GSK3fl at many of the sites we observed in transfected cells, GSK3fl probably was directly responsible for the increased immunoreactivities and mobility shifts observed here.”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
What the sources say
- Not checked — no full text of the sourcecites [7] Hanger, 1992, Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localization of the kinase, Neurosci. Lett. source
- Supportedcites [12] Mandelkow, 1992, Glycogen synthase kinase 3 and the Alzheimer's disease-like state of microtubule-associated protein tau, FEBS Lett. source
The Materials and Methods passage identifies several tau sites phosphorylated by GSK3, including Ser-199, Ser-202, Ser-396 and Ser-404. Figure 2 and the accompanying section report changes in antibody reactivity and an electrophoretic mobility shift after in vitro GSK3 treatment. The conclusion about the citing authors’ transfected cells is their inference, not a result attributed to this source. (LLM, conf=0.89)
- Not checked — no full text of the sourcecites [14] Paudel, 1993, Brain prolinedirected protein kinase phosphorylates tau on sites that are abnormally phosphorylated in tau associated with Alzheimer's paired helical filaments, J. Biol. Chem. source
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.
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
“Phosphorylation of tau at this site caused an increase in PHF1 and T3P immunoreactivities, as well as a decrease in electrophoretic mobility relative to mock-transfected CHO T40 or CHO T44 cells and human fetal tau standards (Fig. 3C,D).”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
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.
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
“Similar results were obtained for tau phosphorylation at Thr-181, Ser-202 and Thr-231.”
- Also stated in: § GSK3I]S9Amyc: · plain
“Increased AT270 (Fig. 2G,H), AT180 (Fig. 2I,J) and AT8 (Fig. 2K,L) staining in transiently transfected CHO T40 was observed by indirect immunofluorescence.”
- Also stated in: § GSK3I]S9Amyc: · plain
“Furthermore, increased phosphorylation at these sites was also observed by immunoblotting of transfected cells (Fig. 3E,F and data not shown).”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
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.
The quote only partly states this claim.
- Also stated in: § GSK3I]S9Amyc: · plain
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
“Approximately 2-10% of cells expressed high levels of GSK3fl.”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
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. The quote only partly states this claim.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Prior studies have shown that many phosphorylated residues in PHF-tau are serines or threonines followed by a proline [1,6,8,11].”
§ NEUROSCI ENCE > Abstract
What the sources say
- Not checked — no full text of the sourcecites [1] Bramblett, 1993, Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding, Neuron source
- Not checked — no full text of the sourcecites [6] Goedert, 1993, The abnormal phosphorylation of tau protein at serine202 in Alz heimer's disease recapitulates phosphorylation during development source
- Not checked — no full text of the sourcecites [8] Hasegawa, 1992, Protein sequence and mass spectrometric analyses of tau in the Alzheimer's disease brain, J. Biol. Chem. source
- Not checked — no full text of the sourcecites [11] Lee, 1991, A68: a major subunit of paired helical filaments and derivatized forms of normal tau, Science source
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.
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
“Thus, the net increase in tau phosphorylation as detected by immunoblot is modest since only a subset of the tau proteins are phosphorylated by GSK3fl.”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
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.
In the paper
“Hyperphosphorylated tau protein is the major constituent of the paired helical filament (PHF), the major fibrous component of the neurofibrillary lesions of Alzheimer's disease (AD).”
- Also stated in: § Abstract · boosted
“The major fibrous component of the neurofibrillary lesions is the paired helical filament (PHF) which has been shown to be composed of highly phosphorylated forms of microtubuleassociated protein tau (PHF-tau).”
§ NEUROSCI ENCE > Abstract
What the sources say
- Not matchedcites [18] Trojanowski, 1993, PHFτ (A68): from pathological marker to potential mediator of neuron dysfunction and degen eration in Alzheimer's disease, Clin. Neurosci.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosted- 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.
- Also stated in: § Abstract · boosted
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 suffer from the inherent limitation that in vitro studies are not necessarily representative of in vivo events.”
§ NEUROSCI ENCE > Abstract
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
In the paper
“CHO cell lines stably expressing either three-repeat tau (CHO T44) or two N-terminal insert four-repeat tau (CHO T40) were prepared as described [1] and >95% of the CHO T44 and CHO T40 cells express high levels of these tau proteins.”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
What the sources say
- Not checked — no full text of the sourcecites [1] Bramblett, 1993, Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding, Neuron 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.
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 fact that both isoforms of tau showed similar immunoreactivities also suggests that the activity of GSK3fl in CHO cells was not isoformspecific.”
§ NEUROSCI ENCE > GSK3I]S9Amyc:
hedged- 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.
It may state two separate claims as one.
The paper relies on this without support.
Hyperphosphorylation of tau is the critical event leading to filament assembly.
“Hyperphosphorylation of tau is believed to be the critical event that leads to filament assembly.”
The paper relies on this without support.
Findings in GSK3β-transfected CHO cells are relevant to GSK3β-mediated tau phosphorylation in vivo.
“The model system used here does not represent physiological conditions, but we used it to further understand how the phosphorylation of tau is regulated in the normal and AD brain.”
“They extend results obtained in vitro [7,12,14] to an in vivo model system, and indicate that GSK3fl may be involved in the phosphorylation of tau in vivo.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“GSK3 is a proline-directed kinase that contributes to phosphorylation of tau at serine or threonine followed by proline (i.e., SP/TP sites) [46–49]”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [48]
Experimental — accuracy not yet measured
Citations
Cites
A68: a Major Subunit of Paired Helical Filaments and Derivatized Forms of Normal Tau
Lee, V. M.-Y., Balin, B. J., Otvos, L., & Trojanowski, J. Q. (1991) · Science · doi:10.1126/science.1899488 · Cited by 1,418
Self-citationMolecular cloning and expression of glycogen synthase kinase‐3/factor A.
Woodgett, J. R. (1990) · The EMBO Journal · doi:10.1002/j.1460-2075.1990.tb07419.x · Cited by 1,362
Embi, N., Rylatt, D. B., & Cohen, P. (1980) · PubMed · Cited by 911
Sutherland, C., Leighton, I. A., & Cohen, P. (1993) · Biochemical Journal · doi:10.1042/bj2960015 · Cited by 903
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
Self-citationGlycogen Synthase Kinase‐3 from Rabbit Skeletal Muscle
Noor, E. M. B. I., RYLATT, D. B., & Cohen, P. (1980) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1980.tb06059.x · Cited by 837
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Monoclonal antibody PHF‐1 recognizes tau protein phosphorylated at serine residues 396 and 404
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Self-citationInsulin and Insulin-like Growth Factor-1 Regulate Tau Phosphorylation in Cultured Human Neurons
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Self-citationMolecular Targets of Lithium Action
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RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice
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“GSK-3 , by virtue of its role as a major tau kinase (Lovestone et al., 1994; Sperber et al., 1995; Zheng-The Effect of Tau Misexpression on Neural Development and Cell Fate Fischhofer et al., 1998), its formation of a complex with tau in the microtubule fraction from bovine brain (SunExamination of…”
BackgroundLithium Reduces Tau Phosphorylation by Inhibition of Glycogen Synthase Kinase-3
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Self-citationDrosophila as a Model for Human Neurodegenerative Disease
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Colocalization of Tau and Alpha-Synuclein Epitopes in Lewy Bodies
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Phosphorylation Sites on Tau Identified by Nanoelectrospray Mass Spectrometry
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“…European Molecular Biology Organization The EMBO Journal VOL 23 | NO 13 | 2004 2591 PS1 / fibroblasts with the longest human tau isoform and then examined phosphorylation of tau residues Ser396/404 and Ser202 that are targets of GSK-3b and are overphosphorylated in AD brains (Sperber et al, 1995).”
BackgroundCho, J., & Johnson, G. V. W. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02155.x · Cited by 282
Effects of Wnt Signaling on Proliferation and Differentiation of Human Mesenchymal Stem Cells
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“The phosphorylation status of transfected tau has now been studied in a variety of different cell types including 3T3 and CHO cells (Gallo et al., 1992; Bramblett et al., 1993; Sygowski et al., 1994; Preuss et al., 1995; Sperber et al., 1995).”
InfluentialEsposito, G., Filippis, D. D., Carnuccio, R., Izzo, A. A., & Iuvone, T. (2005) · Journal of Molecular Medicine · doi:10.1007/s00109-005-0025-1 · Cited by 252
The links between axin and carcinogenesis
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“…dynamics are influenced by GSK-3 activity in neurons (Hanger et al., 1992; Mandelkow et al., 1992; Lovestone et al., 1994; Baum et al., 1995; Sperber et al., 1995; Garcia-Perez et al., 1998; Goold et al., 1999; Sayas et al., 1999; Lucas et al., 2001; Sanchez et al., 2001), the rapid nature…”
BackgroundDevelopmental expression and localization of glycogen synthase kinase-3β in rat brain
Leroy, K., & Brion, J. (1999) · Journal of Chemical Neuroanatomy · doi:10.1016/s0891-0618(99)00012-5 · Cited by 242
Shaw, M., Cohen, P., & Alessi, D. R. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01235-0 · Cited by 231
Pivotal role of glycogen synthase kinase-3: A therapeutic target for Alzheimer's disease
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The Role of Caspase Cleavage of Tau in Alzheimer Disease Neuropathology
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Association Between Autophagy and Neurodegenerative Diseases
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“The phosphorylation of tau by glycogen synthase kinase 3β facilitates its accumulation within the cytosol (Sperber et al., 1995).”
BackgroundPeptidyl-prolyl cis–trans isomerase Pin1 in ageing, cancer and Alzheimer disease
Lee, T. H., Pastorino, L., & Lu, K. P. (2011) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399411001906 · Cited by 185
GSK‐3 in Neurodegenerative Diseases
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“[44] B.”
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Neuronal polarization: The cytoskeleton leads the way
Stieß, M., & Bradke, F. (2010) · Developmental Neurobiology · doi:10.1002/dneu.20849 · Cited by 175
“Interestingly, also APC and CRMP-2 are regulated by GSK3b, emphasizing again microtubules as active players and converging points of polarity regulators (Zhou and Snider, 2005).”
BackgroundInfluentialMaggirwar, S. B., Tong, N., Ramirez, S. H., Gelbard, H. A., & Dewhurst, S. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0730578.x · Cited by 168
Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain
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“The oligomer/NMDA-R/Ca2+ mechanism has been coupled in cell biology studies to aberrant function in glycogen synthase kinase 3 (GSK3 ) [83], which catalyzes tau hyperphosphorylation [62, 85].”
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Normal and Pathological Tau Proteins as Factors for Microtubule Assembly
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Chaperone signalling complexes in Alzheimer's disease
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“Several reports have identified GSK3 as a key player in Alzheimer’s disease (AD) (20) because of its role in promoting tau phosphorylation and tangle formation (21, 22).”
BackgroundA New Molecular Link between the Fibrillar and Granulovacuolar Lesions of Alzheimer's Disease
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Loss of Muscarinic M1 Receptor Exacerbates Alzheimer's Disease–Like Pathology and Cognitive Decline
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“This site seems to be phosphorylated by GSK3 and CDK5; therefore, it is likely that combined activation of both kinases may be necessary to increase phosphorylation of the PHF-1 site.(50,51) In the 3xTg-AD mice, AT270, AT180, and AT100 represent early markers of tau phosphorylation, whereas reactivity with AT8 and PHF…”
BackgroundZhang, X., Heng, X., Li, T., Li, L., Yang, D., Zhang, X., Du, Y., Doody, R. S., & Le, W. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101875 · Cited by 120
“Ser396 in tau is the GSK3 -targeted residue [30, 31].”
Transgenic zebrafish model of neurodegeneration
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“It was shown that introduction of mitogen activated protein (MAP), cyclin dependent kinase (cdk)2, and glycogen synthase kinase (GSK)-3 kinases resulted in the phosphorylation tau on “AD” sites in cultured neurons and COS cells (Lu et al., 1993; Sperber et al., 1995; Baum et al., 1995).”
BackgroundIntracellular pathways underlying the effects of lithium
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“GSK-3b is involved in tau hyperphosphorylation (Sperber et al., 1995) and”
BackgroundDendritic changes in Alzheimer's disease and factors that may underlie these changes
Anderton, B. H., Callahan, L. M., Coleman, P. D., Davies, P., Flood, D. G., Jicha, G. A., Ohm, T. G., & Weaver, C. L. (1998) · Progress in Neurobiology · doi:10.1016/s0301-0082(98)00022-7 · Cited by 113
“Although in vitro studies have been performed with a variety of protein kinases, not all of these kinases seem to phosphorylate tau in cells, GSK-3 being one that is capable of this eect (Sperber et al., 1995; Baum et al., 1995; Lovestone et al., 1994; Latimer et al., 1995).”
Godemann, R., Biernat, J., Mandelkow, E., & Mandelkow�, E. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00741-3 · Cited by 110
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“…and thus its availability for interaction with the presenilins are modulated by glycogen synthase kinase 3b, which phosphorylates the microtubule-associated protein Tau and may be involved in the genesis of neurofibrillary tangles (Sperber et al., 1995; Hong et al., 1997; Imahori and Uchida, 1997).”
Ando, K., Maruko-Otake, A., Ohtake, Y., Hayashishita, M., Sekiya, M., & Iijima, K. M. (2016) · PLOS Genetics · doi:10.1371/journal.pgen.1005917 · Cited by 105
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“neuronal cells through a variety of mechanisms that and lysosomal membrane permeabilization [17, 118] Cannabinoids at physiological concentrations increase lysosomal stability and integrity [148].”
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Fast Axonal Transport Misregulation and Alzheimer's Disease
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Molecular dissection of the paired helical filament
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Phosphorylation of Tau Is Regulated by PKN
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Role of GSK‐3β in Alzheimer's disease pathology
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“Because MAPs are phosphorylated by GSK-3, GSK-3 activation could promote MT reorganization, contributing to LPAinduced mitosis progression and cell rounding in ventricular zone neuroblasts.”
BackgroundInfluentialGlycogen synthase kinase-3β-mediated tau phosphorylation in cultured cell lines
Lee, C. W., Lau, K., Miller, C. C. J., & Shaw, P. (2003) · Neuroreport · doi:10.1097/00001756-200302100-00020 · Cited by 80
Amyloid-β and Tau Pathology of Alzheimer's Disease Induced by Diabetes in a Rabbit Animal Model
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The therapeutic potential of the phytocannabinoid cannabidiol for Alzheimer’s disease
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Calcineurin dephosphorylates glycogen synthase kinase‐3 beta at serine‐9 in neuroblast‐derived cells
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Advances in the Pathogenesis of Alzheimer’s Disease: Focusing on Tau-Mediated Neurodegeneration
Duan, Y., Dong, S., Gu, F., Hu, Y., & Zhao, Z. (2012) · Translational Neurodegeneration · doi:10.1186/2047-9158-1-24 · Cited by 80
“In transfected mammalian cells, GSK3α and GSK3β could contribute to the formation of PHF [36,37].”
BackgroundBuée‐Scherrer, V., & Goedert, M. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)02460-2 · Cited by 76
Self-citationGómez‐Villafuertes, R., del Puerto, A., Dı́az-Hernández, M., Bustillo, D., Díaz‐Hernandéz, J. I., Huerta, P. G., Artalejo, A. R., Garrido, J. J., & Miras‐Portugal, M. T. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.07228.x · Cited by 75
Disruption of the cytoskeleton in Alzheimer's disease
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The Role of Post-Translational Modifications on the Structure and Function of Tau Protein
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“For example, glycogen synthase kinase-3β (GSK-3β) is involved in physiological phosphorylation of tau (Gibb et al. 2000; Sperber et al. 1995; Wang et al. 1998).”
BackgroundSergeant, N., David, J. ‐., Goedert, M., Jakes, R., Vermersch, P., Buée, L., Lefranc, D., Wattez, A., & Delacourte, A. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69020834.x · Cited by 79
Self-citationSHIP2 and its involvement in various diseases
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Benzler, J., Ganjam, G. K., Krüger, M., Pinkenburg, O., Kutschke, M., Stöhr, S., Steger, J., Koch, C. E., Oelkrug, R., Schwartz, M. W., et al. (2012) · Biochemical Journal · doi:10.1042/bj20120834 · Cited by 70
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Modulation of neurite branching by protein phosphorylation in cultured rat hippocampal neurons
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“[57] reported that transient transfection of human GSK-3β in Chinese hamster ovary cell caused an increase in tau phosphorylation at Ser202, Ser396, Ser404, Thr181, and Thr231 sites.”
Aberrant Wnt signaling pathway in medial temporal lobe structures of Alzheimer’s disease
Riise, J., Plath, N., Pakkenberg, B., & Parachikova, A. (2015) · Journal of Neural Transmission · doi:10.1007/s00702-015-1375-7 · Cited by 66
“Here, we characterized the tau phosphorylation pattern of known Gsk3b substrates (Reynolds et al. 2000; Sperber et al. 1995) in soluble and insoluble fractions of the hippocampus present with early tau pathology.”
BackgroundPinning down phosphorylated tau and tauopathies
Lim, J., & Lu, K. P. (2004) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2004.10.003 · Cited by 67
Molecular Cloning and Characterization of the Human Glycogen Synthase Kinase-3β Promoter
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Tumor suppressor PTEN affects tau phosphorylation, aggregation, and binding to microtubules
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“Exposure of cortical neurons to these Wnt negative modulators induced a significantly increase in tau phosphorylation at the Alzheimer-related epitope PHF-1 (Ser) which is known to be susceptible to phosphorylation by GSK-3b [43] (Fig.”
BackgroundGlycogen synthase kinase 3 has a limited role in cell cycle regulation of cyclin D1 levels
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Post-translational modifications of tau protein
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Metadata
- Authors
- Sperbera, B. R., Leight, S., Goedert, M., & Lee, V. M.-Y.
- Affiliations
- University of Pennsylvania (US)
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Lee, V.M.-Y.
- ORCID
- Goedert, Michel
- Venue
- Neuroscience Letters
- Publisher
- Elsevier BV
- Published
- 1995-09
- Volume
- 197
- Issue
- 2
- Pages
- 149-153
- ISSN
- 0304-3940 (ISSN-L)
- OpenAlex
- W2078680897
- Semantic Scholar
- b65c92714a748a00c0908686620cc4d7ab64e748
- Cited by
- 204
- References
- 19
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 9 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 10 · 2015: 6 · 2014: 5 · 2013: 6 · 2012: 7
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuroscience Letters (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- glycogen synthase kinase-3β, tau protein, tau hyperphosphorylation, paired helical filaments, Alzheimer's disease, neurofibrillary tangles, protein kinases, tau isoforms, mitogen-activated protein kinase, phosphorylation sites
- MeSH terms
- Alanine, Amino Acid Sequence, Animals, Cricetinae, Humans, Molecular Sequence Data, Mutation, Phosphorylation, Serine, Transfection, Immunoblotting, CHO Cells, tau Proteins, Calcium-Calmodulin-Dependent Protein Kinases, Fluorescent Antibody Technique, Indirect, Glycogen Synthase Kinases, Glycogen Synthase Kinase 3
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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