CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer’s Disease
Open accessAbstract
Protein phosphatase 2A (PP2A) inhibition causes hyperphosphorylation of tau and APP in Alzheimer's disease (AD). However, the mechanisms underlying the downregulation of PP2A activity in AD brain remain unclear. We demonstrate that Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is overexpressed in AD brain. CIP2A-mediated PP2A inhibition drives tau/APP hyperphosphorylation and increases APP β-cleavage and Aβ production. Increase in CIP2A expression also leads to tau mislocalization to dendrites and spines and synaptic degeneration. In mice, injection of AAV-CIP2A to hippocampus induced AD-like cognitive deficits and impairments in long-term potentiation (LTP) and exacerbated AD pathologies in neurons. Indicative of disease exacerbating the feedback loop, we found that increased CIP2A expression and PP2A inhibition in AD brains result from increased Aβ production. In summary, we show that CIP2A overexpression causes PP2A inhibition and AD-related cellular pathology and cognitive deficits, pointing to CIP2A as a potential target for AD therapy.
AI snapshot
Written from the paper’s full text.
TL;DR
CIP2A, an endogenous PP2A inhibitor, is overexpressed in Alzheimer’s disease brain and Aβ-treated neurons, where it drives PP2A inhibition, tau/APP hyperphosphorylation, APP β-cleavage, Aβ production, synaptic degeneration, and memory deficits. The paper proposes a vicious cycle in which Aβ induces CIP2A, which further inhibits PP2A and exacerbates AD-like pathology.
Key findings
- CIP2A protein levels were increased in frontal and temporal cortex of AD human brains compared with age-matched controls; Aβ treatment induced dose-dependent CIP2A expression and PP2A catalytic inhibition in cultured neurons.
- CIP2A overexpression inhibited PP2A, promoted APP T668 phosphorylation, β-cleavage (increased sAPPβ), and Aβ production without changing PS1 or BACE1; these effects were reversed by PP2A overexpression, and APP-T668A mutation blocked CIP2A-induced β-secretase processing.
- CIP2A promoted tau hyperphosphorylation at S396 and S404 via PP2A inhibition; PP2A overexpression reversed it, while CIP2A shRNA activated PP2A and dephosphorylated tau. CIP2A also increased tau in soma, dendrites, and spines and reduced spine number, PSD95, GluA1, surface GluA1, and AMPAR mEPSC frequency and amplitude.
- In C57/BL6 mice (8–10 weeks) with bilateral intrahippocampal AAV-CIP2A, CIP2A overexpression impaired long-term novel object recognition at 24 hr, impaired Morris water maze learning (longer latency on days 5 and 6) and probe performance at 1 and 48 hr, reduced fear-conditioning freezing, reduced hippocampal LTP, decreased spine density, and downregulated synapsin, synaptophysin, GluA1, and PSD95.
Methods
- Human brain tissues were obtained from the NIH NeuroBioBank; cell models included HEK293-T cells, SH-SY5Y cells, and primary rat cortical/hippocampal neurons treated with Aβ or transfected/infected with CIP2A, PP2A, APP, tau, or shRNA/siRNA constructs.
- In vivo experiments used Sprague-Dawley rats and C57 mice; mice received bilateral intrahippocampal AAV-Con or AAV-CIP2A, followed by fluorescence confirmation, biochemical assays, behavior tests (novel object recognition, Morris water maze, fear conditioning), LTP recordings, patch-clamp electrophysiology, and Golgi staining.
- Main analyses included Western blotting, co-immunoprecipitation, PP2A activity assays, Aβ40/42 ELISA, fluorescence/confocal imaging, synaptosome fractionation, and electrophysiology; data are expressed as mean ± SEM and analyzed with one-way ANOVA or Student’s t test, with significance at p < 0.05.
Limitations
- The paper does not state a dedicated limitations section.
- Evident from the text: human AD findings are correlative and based on frontal/temporal cortex samples without reported sample sizes or detailed clinical/demographic matching beyond “age-matched controls.”
- Evident from the text: many mechanistic conclusions rely on overexpression systems (CIP2A transfection/lentivirus/AAV) and acute Aβ treatment; the in vivo studies use CIP2A overexpression rather than CIP2A loss-of-function rescue in AD mouse models, and the upstream cause of CIP2A upregulation in human AD is stated as needing further exploration.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 44 cited sources checked · 0 supported · 0 flagged
- Findingown data
In Morris water maze test trials at 1 and 48 hr, CIP2A mice showed decreased swimming time in the target quadrant compared with control mice.
“In the test trials at both 1 and 48 hr, CIP2A mice showed decreased crossing times and swimming time in the target quadrant compared with the control mice, with no changes in swimming speed (Figures 4I–4K).”
Quote in the paperSubstantial claim - Findingown data
In HEK293-T cells co-transfected with CIP2A and APP-T668A mutant, CIP2A failed to promote β-secretase processing of APP.
“Under this condition, CIP2A failed to promote β-secretase processing of APP (Figures 2G–2J).”
Quote in the paperSubstantial claim - Findingown data
The CIP2A-inducing effects of recombinant Aβ can be recapitulated by endogenous APP overexpression in SH-SY5Y cells.
“We also demonstrate that the CIP2A-inducing effects of recombinant Aβ can be recapitulated by endogenous APP overexpression in SH-SY5Y cells (Figure 1G).”
Quote in the paperSubstantial claim - Findingown data
CIP2A increases Aβ production.
“CIP2A also increased Aβ production (Figures 2E and 2F).”
Quote in the paperSubstantial claim - Findingown data
Surface GluA1 is significantly reduced in CIP2A-overexpressing neurons.
“A significant reduction of spine number and surface GluA1 was observed in CIP2A-overexpressing neurons (Figure 3H).”
Quote in the paperSubstantial claim
- Findingown data
CIP2A promotes APP T668 phosphorylation.
“CIP2A promoted APP T668 phosphorylation and β-cleavage (increased sAPPβ), but did not affect the expression of PS1 and BACE1 (Figures 2C and 2D).”
Quote in the paperSubstantial claim - Findingown data
In the novel object recognition test, the recognition index was comparable between control and CIP2A mice in the acquisition trial.
“In the novel object recognition test (NOR), the recognition index was comparable between the control and CIP2A mice (Figures 4B and 4C) in the acquisition trial.”
Quote in the paperNot a substantial claim - Findingown data
CIP2A expression levels are increased in the frontal and temporal cortex in AD human brains compared with age-matched controls.
“we found that CIP2A expression levels were increased in the frontal and temporal cortex in AD human brains compared with age-matched controls (Figures 1A and 1B).”
Quote in the paperSubstantial claim - Findingown data
In Morris water maze test trials at 1 and 48 hr, CIP2A mice showed decreased crossing times in the target quadrant compared with control mice.
“In the test trials at both 1 and 48 hr, CIP2A mice showed decreased crossing times and swimming time in the target quadrant compared with the control mice, with no changes in swimming speed (Figures 4I–4K).”
Quote in the paperSubstantial claim - Findingown data
The amount of tau at spines is significantly increased in cultured hippocampal neurons transfected with GFP-tau and infected with CIP2A lentivirus.
“Analysis of GFP-tau in the spines indicated that the amount of tau at the spines was significantly increased (Figure 3E).”
Quote in the paperSubstantial claim - Findingown data
The frequency of AMPAR-mediated mEPSC is reduced in CIP2A-transfected neurons.
“in CIP2A-transfected neurons, patch-clamp recordings showed a reduction in the frequency and amplitude of the AMPAR-mediated miniature excitatory postsynaptic current (mEPSC) (Figure 3I).”
Quote in the paperSubstantial claim - Findingown data
In CIP2A-overexpressing mouse hippocampus, tau phosphorylation is increased.
“We also confirmed the increased tau and APP phosphorylation, as well as the increase in Aα40 and Aα42 levels in hippocampus (Figures S2A-SSE).”
Quote in the paperSubstantial claim - Findingown data
In Aβ-treated primary neurons, CIP2A knockdown reverses Aβ-induced APP and tau hyperphosphorylation.
“in Aβ-treated primary neurons, CIP2A knockdown effectively reversed Aβ-induced APP and tau hyperphosphorylation.”
Quote in the paperSubstantial claim - Findingown data
The effect of CIP2A-induced tau hyperphosphorylation is reversed by overexpression of PP2A.
“The effect of CIP2A-induced tau hyperphosphorylation was reversed by overexpression of PP2A (Figure 2M).”
Quote in the paperSubstantial claim - Findingown data
Aβ-induced CIP2A protein expression is accompanied by dose-dependent inhibition of PP2A catalytic activity in cultured neurons.
“Importantly, the Aβ-induced CIP2A protein expression was reflected in similarly dose-dependent inhibition of PP2A catalytic activity in cultured neurons (Figures 1C–1F).”
Quote in the paperSubstantial claim - Findingown data
Knockdown of CIP2A by shRNA results in tau dephosphorylation.
“knockdown of CIP2A by short hairpin RNA (shRNA) resulted in PP2A activation and tau dephosphorylation (Figures S1A-S1C).”
Quote in the paperSubstantial claim - Findingown data
CIP2A-induced hyperphosphorylated tau is detected at axons, soma, and dendrites.
“CIP2A overexpression induced a marked increase in tau phosphorylation; the intensive AD-like hyperphosphorylated tau was detected not only at axons, but also at the soma and dendrites (Figures 3A–3C).”
Quote in the paperSubstantial claim - Findingown data
CIP2A overexpression results in PP2A inhibition in HEK293-T cells.
“we found that CIP2A overexpression resulted in PP2A inhibition, indicated by PP2A activity assay via measuring the dephosphorylation of a synthesized general substrate of PP2A (Figure 2A).”
Quote in the paperSubstantial claim - Findingown data
CIP2A-induced PP2A inhibition is accompanied by tau hyperphosphorylation at S396 and S404.
“CIP2A-induced PP2A inhibition (Figure 2L) was accompanied by tau hyperphosphorylation at S396 and S404 (Figure 2M), both typical phosphorylation sites involved in AD.”
Quote in the paperSubstantial claim- Rests on an assumption: Phosphorylation sites S396 and S404 of tau are typical sites involved in AD.
- Findingown data
Knockdown of CIP2A by shRNA results in PP2A activation.
“knockdown of CIP2A by short hairpin RNA (shRNA) resulted in PP2A activation and tau dephosphorylation (Figures S1A-S1C).”
Quote in the paperSubstantial claim - Findingown data
CIP2A promotes APP β-cleavage, increasing sAPPβ.
“CIP2A promoted APP T668 phosphorylation and β-cleavage (increased sAPPβ), but did not affect the expression of PS1 and BACE1 (Figures 2C and 2D).”
Quote in the paperSubstantial claim - Findingown data
Aβ treatment induces a dose-dependent increase in CIP2A protein expression in cultured neurons.
“Aβ treatment induced a dose-dependent increase in CIP2A protein expression in cultured neurons, with no obvious signs of toxicity.”
Quote in the paperSubstantial claim - Findingown data
In CIP2A-overexpressing mouse hippocampus, Aα40 and Aα42 levels are increased.
“We also confirmed the increased tau and APP phosphorylation, as well as the increase in Aα40 and Aα42 levels in hippocampus (Figures S2A-SSE).”
Quote in the paperSubstantial claim - Findingown data
The amplitude of AMPAR-mediated mEPSC is reduced in CIP2A-transfected neurons.
“in CIP2A-transfected neurons, patch-clamp recordings showed a reduction in the frequency and amplitude of the AMPAR-mediated miniature excitatory postsynaptic current (mEPSC) (Figure 3I).”
Quote in the paperSubstantial claim - Findingown data
In CIP2A-overexpressed mice, there is a marked decline in spine density compared with control mice.
“In CIP2A-overexpressed mice, we observed a marked decline in spine density compared with the control mice (Figures 5D and 5E).”
Quote in the paperSubstantial claim - Findingown data
CIP2A-induced changes in APP T668 phosphorylation, β-cleavage, and Aβ production are reversed by overexpressing PP2A.
“Consistent with the involvement of PP2A, all of these changes were reversed by overexpressing PP2A (Figures 2C–2F).”
Quote in the paperSubstantial claim - Findingown data
In fear conditioning test, CIP2A mice showed a significant reduction in freezing time in both contextual and tone conditioning paradigms.
“Consistently, in the fear conditioning test, CIP2A mice showed a significant reduction in freezing time in both the contextual and the tone conditioning paradigms (Figure S3).”
Quote in the paperSubstantial claim - Findingown data
Expression of CIP2A significantly reduced the magnitude of LTP in the CA3-to-CA1 circuit in hippocampal slices from CIP2A-overexpressing mice.
“compared with the control, expression of CIP2A significantly reduced the magnitude of LTP, indicating a deleterious effect of CIP2A upregulation on synaptic plasticity (Figures 5A-5C).”
Quote in the paperSubstantial claim - Findingown data
In CIP2A-overexpressed mice, levels of postsynaptic proteins GluA1 and PSD95 are downregulated.
“a downre-gulation was observed in the levels of pre-synaptic proteins synapsin and synaptophysin, as well as postsynaptic proteins including GluA1 and PSD95 (Figures 5F and 5G; Table 1).”
Quote in the paperSubstantial claim - Findingown data
In test trials 24 hr after acquisition, recognition index to the new object was significantly decreased in CIP2A mice.
“However, in the test trials 24 hr after the acquisition trial, recognition index to the new object was significantly decreased in the CIP2A mice (Figure 4E), indicating impaired long-term memory.”
Quote in the paperSubstantial claim - Findingown data
CIP2A does not affect the expression of PS1 and BACE1.
“CIP2A promoted APP T668 phosphorylation and β-cleavage (increased sAPPβ), but did not affect the expression of PS1 and BACE1 (Figures 2C and 2D).”
Quote in the paperNot a substantial claim - Findingown data
In Morris water maze acquisition training, CIP2A mice showed impaired learning, indicated by significantly longer latency at days 5 and 6.
“In the acquisition training phase, CIP2A mice showed impaired learning, which was indicated by significantly longer latency at the last 2 days (days 5 and 6; Figure 4H).”
Quote in the paperSubstantial claim - Findingown data
CIP2A overexpression induces a marked increase in tau phosphorylation in mature cultured hippocampal neurons.
“CIP2A overexpression induced a marked increase in tau phosphorylation; the intensive AD-like hyperphosphorylated tau was detected not only at axons, but also at the soma and dendrites (Figures 3A–3C).”
Quote in the paperSubstantial claim - Findingown data
In CIP2A-overexpressed mice, levels of pre-synaptic proteins synapsin and synaptophysin are downregulated.
“a downre-gulation was observed in the levels of pre-synaptic proteins synapsin and synaptophysin, as well as postsynaptic proteins including GluA1 and PSD95 (Figures 5F and 5G; Table 1).”
Quote in the paperSubstantial claim - Findingown data
In CIP2A-overexpressing mouse hippocampus, APP phosphorylation is increased.
“We also confirmed the increased tau and APP phosphorylation, as well as the increase in Aα40 and Aα42 levels in hippocampus (Figures S2A-SSE).”
Quote in the paperSubstantial claim - Findingown data
The number of spines is decreased significantly in neurons overexpressing CIP2A.
“The number of spines was decreased significantly in neurons overexpressing CIP2A (Figure 3F).”
Quote in the paperSubstantial claim - Findingown data
Post-synaptic proteins including PSD95 and GluA1 are decreased in CIP2A-overexpressing neurons.
“Furthermore, the post-synaptic proteins including PSD95 and GluA1 were decreased (Figure 3G).”
Quote in the paperSubstantial claim - Findingown data
The level of hyperphosphorylated tau is significantly increased in synaptosomal lysates from CIP2A-overexpressing neurons.
“Using synaptosomal lysates isolated from cultured neurons, we found that the level of hyperphosphorylated tau was significantly increased in CIP2A-overexpressing neurons (Figure 3D).”
Quote in the paperSubstantial claim - Findingown data
In Morris water maze test trials, CIP2A mice showed no changes in swimming speed.
“In the test trials at both 1 and 48 hr, CIP2A mice showed decreased crossing times and swimming time in the target quadrant compared with the control mice, with no changes in swimming speed (Figures 4I–4K).”
Quote in the paperSubstantial claim - Findingown data
Mislocalization of tau, especially hyperphosphorylated tau, is accompanied by synaptic degeneration indicated by a decrease in spine numbers and synaptic proteins including AMPARs.
“Also, we found that the mislocalization of tau (especially hyperphosphorylated tau) was accompanied by synaptic degeneration indicated by a decrease in spine numbers and synaptic proteins including AMPARs.”
Quote in the paperSubstantial claim - Findingown data
In primary neurons, CIP2A promotes tau translocalization to dendrites and spines.
“In primary neurons, we further observed that CIP2A promoted tau translocalization to dendrites and spines, which is considered to be the key event mediating the synaptic toxicity of tau (Pooler et al., 2014; Zempel et al., 2013).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
PP2A inhibition causes hyperphosphorylation of tau and APP in Alzheimer's disease.
“Protein phosphatase 2A (PP2A) inhibition causes hy-perphosphorylation of tau and APP in Alzheimer’s disease (AD).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
In Alzheimer's disease patient brains, PP2A activities were decreased.
“In Alzheimer’s disease (AD) patient brains, PP2A activities were decreased (Gong et al., 1993, 1995).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gong et al., 1993, 1995
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Inhibition of PP2A in cultured brain slices and rat brains induced tau hyperphosphorylation at multiple sites known to be related to AD.
“Inhibition of PP2A in cultured brain slices and rat brains induced tau hyperphosphorylation at multiple sites known to be related to AD (Gong et al., 2000; Sun et al., 2003).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
The stimulating effect of CIP2A on APP β-cleavage requires APP-T668 phosphorylation induced by PP2A inhibition.
“Thus, the stimulating effect of CIP2A on APP β-cleavage requires APP-T668 phosphorylation induced by PP2A inhibition.”
Quote in the paperSubstantial claim - Interpretationown data
In vivo, elevated expression of CIP2A induces aberrant alterations that mimic pathologies in AD.
“These data indicate that in vivo in the brain, elevated expression of CIP2A induces aberrant alterations that mimic pathologies in AD.”
Quote in the paperSubstantial claim - Interpretationown data
CIP2A promotes β-cleavage of APP by inhibiting PP2A.
“These findings suggest that CIP2A promotes β-cleavage of APP by inhibiting PP2A.”
Quote in the paperSubstantial claim - Premisecitation
Modulation of PP2A activity in transgenic mouse models supports a causative role for PP2A inhibition in AD pathologies.
“even though modulation of PP2A activity in transgenic mouse models (Nicholls et al., 2016) further supports the causative role for PP2A inhibition in AD pathologies”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nicholls et al., 2016 source
Not checked in the free run.
- Interpretationown data
CIP2A overexpression induces deficits in visual episodic memory.
“These results show that CIP2A overexpression induces deficits in visual episodic memory.”
Quote in the paperSubstantial claim - Interpretationown data
CIP2A promotes tau hyperphosphorylation through PP2A inhibition.
“These results indicate that CIP2A promotes tau hyperphosphorylation through PP2A inhibition.”
Quote in the paperSubstantial claim - Interpretationown data
CIP2A induces learning and memory deficits.
“Together, these results indicate that CIP2A induces learning and memory deficits.”
Quote in the paperSubstantial claim - Interpretationown data
Aβ is an initial factor that induces CIP2A upregulation in AD brains.
“These data strongly indicate that Aβ is an initial factor that induces CIP2A upregulation in AD brains.”
Quote in the paperSubstantial claim - Interpretationown data
Elevated amount of CIP2A causes synaptic degeneration in mice.
“Taking together, these results demonstrate that an elevated amount of CIP2A causes synaptic degeneration in mice.”
Quote in the paperSubstantial claim - Interpretationown data
CIP2A upregulation has a deleterious effect on synaptic plasticity.
“indicating a deleterious effect of CIP2A upregulation on synaptic plasticity”
Quote in the paperSubstantial claim - Premisecitation
Mice expressing mutated human APP and mutated human tau develop several-fold increased neurofibrillary tangles compared with mice expressing only mutated human tau.
“Mice expressing mutated human APP and mutated human tau develop several-fold increased neurofibrillary tangles, compared with mice expressing only mutated human tau (Lewis et al., 2001).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lewis et al., 2001 source
Not checked in the free run.
- Interpretationown data
CIP2A promotes translocation of hyperphosphorylated tau into the synapse.
“Thus, CIP2A promoted translocation of hyperphosphorylated tau into the synapse.”
Quote in the paperSubstantial claim - Interpretationown data
Increased CIP2A expression and PP2A inhibition in AD brains result from increased Aβ production.
“Indicative of disease exacerbating the feedback loop, we found that increased CIP2A expression and PP2A inhibition in AD brains result from increased Aβ production.”
Quote in the paperSubstantial claim - Study design and conductown data
Overexpression of CIP2A in the hippocampus was confirmed by fluorescence microscopy 4 weeks after injection.
“Overexpression of CIP2A in the hippocampus was confirmed by fluorescence microscopy 4 weeks after injection (Figure 4A).”
Quote in the paperSubstantial claim - Interpretationown data
CIP2A causes disruption in spatial learning and memory.
“These results suggest that CIP2A causes disruption in spatial learning and memory.”
Quote in the paperSubstantial claim - Interpretationreasoning
The observed abnormalities in synapse formation and function may serve as the mechanisms underlying CIP2A/PP2A-dependent tau pathology and cognitive deficits.
“the observed abnormalities in synapse formation and function may serve as the mechanisms underlying CIP2A/PP2A-dependent tau pathology and cognitive deficits.”
Quote in the paperSubstantial claim - Premisecitation
Neurons without tau are resistant to Aβ toxicity.
“Neurons without tau are resistant to Aβ toxicity, and APP transgenic mice lacking tau develop Aβ pathology but remain cognitively normal (Rapoport et al., 2002; Roberson et al., 2007).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
The inhibitory effect of CIP2A on PP2A is substrate dependent; CIP2A inhibits PP2A activity only toward certain substrates without influencing phosphorylation of other substrates.
“Second, the inhibitory effect of CIP2A on PP2A is substrate dependent. CIP2A inhibits the PP2A activity only toward a certain number of substrates without influencing the phosphorylation of other substrates.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Junttila et al., 2007 source
Not checked in the free run.
- Premisecitation
Aβ induces oxidative DNA damage.
“With the recognized knowledge that Aβ induces oxidative DNA damage (Suberbielle et al., 2013; Wu et al., 2014; Yan et al., 2014)”
Quote in the paperSubstantial claim0 of 3 sources checked
- May combine two claims. 21
- Classified as probably not a substantial claim. 18
May combine two claims.
Findingown dataCIP2A interacts with PP2A and tau.
“we co-transfected CIP2A and tau plasmids into HEK293-T cells and revealed the interaction of CIP2A, PP2A, and tau by CoIP (Figure 2K).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the test trial 1 hr after acquisition, both groups showed increased interest to the new object with comparable recognition index.
“In the test trial 1 hr after the acquisition trial, mice in both groups showed increased interest to the new object with comparable recognition index (Figure 4D).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataCIP2A interacts with PP2A and APP.
“interaction of CIP2A with PP2A and APP was confirmed by co-immunoprecipitation (CoIP) assays (Figure 2B).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPP2A contributed 71% of the dephosphorylation of human hyperphosphorylated tau isolated from AD patient brains.
“In vitro analysis of the dephosphorylation ability of different phosphatases toward tau showed that PP2A contributed 71% of the dephosphorylation of human hyperphosphorylated tau isolated from AD patient brains (Liu et al., 2005).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Liu et al., 2005 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIncubation of PP2A with hyperphosphorylated tau resulted in tau dephosphorylation and restoration of tau function in promoting microtubule assembly.
“Incubation of PP2A with hyperphosphorylated tau resulted in tau dephosphorylation and restoration of tau function in promoting microtubule assembly (Wang et al., 1995).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wang et al., 1995 source
Not checked in the free run.
May combine two claims.
Interpretationown dataCIP2A-mediated PP2A inhibition drives tau/APP hyperphosphorylation and increases APP β-cleavage and Aβ production.
“CIP2A-mediated PP2A inhibition drives tau/APP hyperphosphorylation and increases APP β-cleavage and Aβ production.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCIP2A is upregulated in a variety of peripheral tumors, leading to inhibition of PP2A activity.
“Cancerous Inhibitor of PP2A (CIP2A) has been shown to be upregulated in a variety of peripheral tumors, leading to an inhibition of PP2A activity (Junttila et al., 2007; Soo Hoo et al., 2002; Khanna et al., 2013a).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Interpretationown dataCIP2A promotes APP β-cleavage and tau hyperphosphorylation through PP2A inhibition.
“Taken together, CIP2A promotes APP β-cleavage and tau hyperphosphorylation through PP2A inhibition.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCIP2A could promote self-renewal and proliferation of mouse neural progenitor cells in vitro.
“One study reported that CIP2A could promote self-renewal and proliferation of mouse neural progenitor cells in vitro (Kerosuo et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kerosuo et al., 2010 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAβ induces tau filament formation in mouse brain.
“Aβ induces tau filament formation in mouse brain (Götz et al., 2001).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Götz et al., 2001
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCIP2A has a role in the development of astrocytoma.
“Another study suggested a role of CIP2A in the development of astrocytoma (Yi et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yi et al., 2013
Not checked in the free run.
May combine two claims.
Interpretationown dataIncrease in CIP2A expression leads to tau mislocalization to dendrites and spines and synaptic degeneration.
“Increase in CIP2A expression also leads to tau mislocalization to dendrites and spines and synaptic degeneration.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataElevated expression of CIP2A results in abnormalities in synaptogenesis and synaptic function.
“These results collectively indicate that elevated expression of CIP2A results in abnormalities in synaptogenesis and synaptic function.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationPP2A inactivation is implicated in promoting phosphorylation of APP at T668 and Aβ over-production.
“Furthermore, PP2A inactivation is also implicated in promoting phosphorylation of amyloid precursor protein (APP) at T668 and Aβ over-production (Sontag et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sontag et al., 2007 source
Not checked in the free run.
May combine two claims.
Interpretationown dataIn mice, injection of AAV-CIP2A to hippocampus induced AD-like cognitive deficits and impairments in LTP and exacerbated AD pathologies in neurons.
“In mice, injection of AAV-CIP2A to hippocampus induced AD-like cognitive deficits and impairments in long-term potentiation (LTP) and exacerbated AD pathologies in neurons.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationAβ and tau interact to either cause or facilitate the pathogenesis of AD.
“An increasing amount of evidence suggests that Aβ and tau interact to either cause or facilitate the pathogenesis of AD (Ittner and Götz, 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ittner and Götz, 2011
Not checked in the free run.
May combine two claims.
Interpretationown dataCIP2A overexpression causes PP2A inhibition and AD-related cellular pathology and cognitive deficits.
“we show that CIP2A overexpression causes PP2A inhibition and AD-related cellular pathology and cognitive deficits, pointing to CIP2A as a potential target for AD therapy.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCIP2A is expressed in normal adult human and mouse brains, especially in olfactory bulb and hippocampus.
“CIP2A is also expressed in normal adult human and mouse brains, especially in olfactory bulb and hippocampus (Kerosuo et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kerosuo et al., 2010 source
Not checked in the free run.
May combine two claims.
Interpretationown dataCIP2A promotes tau phosphorylation and accumulation in soma and dendritic spines.
“These findings support the idea that CIP2A promotes tau phosphorylation and accumulation in soma and dendritic spines.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationIn cancer cells, CIP2A expression is driven by constitutive DNA-damage signaling.
“In cancer cells, CIP2A expression is driven by constitutive DNA-damage signaling (Khanna et al., 2013b).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Khanna et al., 2013b
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDNA damage is a common event in aging.
“With DNA damage as a common event in aging (Lu et al., 2004)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lu et al., 2004
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationPP2A inactivation is regarded as the most important molecular event that causes abnormal tau hyperphosphorylation in the AD brain.
“PP2A inactivation is regarded as the most important molecular event that causes abnormal tau hyperphosphorylation in the AD brain (Iqbal et al., 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Iqbal et al., 2016 source
Not checked in the free run.
May combine two claims.
PremisecitationAPP transgenic mice lacking tau develop Aβ pathology but remain cognitively normal.
“Neurons without tau are resistant to Aβ toxicity, and APP transgenic mice lacking tau develop Aβ pathology but remain cognitively normal (Rapoport et al., 2002; Roberson et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Roberson et al., 2007 source
Not checked in the free run.
May combine two claims.
InterpretationcitationTau pathology may combine with or be downstream of Aβ to cause cognitive deficits.
“These observations suggest that tau pathology may combine with or downstream of Aβ to cause cognitive deficits.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAltered cellular location of endogenous PP2A inhibitors was reported to induce PP2A inactivation in cytoplasm.
“In addition, an altered cellular location of endogenous PP2A inhibitors was reported to induce PP2A inactivation in cytoplasm (Tanimukai et al., 2005).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Tanimukai et al., 2005 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationCombined reduction of both Aβ and tau, but not Aβ alone, improves cognition in a mouse model with both plaques and tangles.
“A combined reduction of both Aβ and tau, but not Aβ alone, was found to improve cognition in a mouse model with both plaques and tangles (Oddo et al., 2004).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Oddo et al., 2004 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationImpaired methylation of the Leu309 site of PP2Ac may decrease the interaction of PP2Ac with PP2A Bα and reduce the level of PP2ABαC holoenzyme, which is the main form of PP2A for tau dephosphorylation.
“Sontag et al. (2004a, 2004b) reported that, in AD brains, impaired methylation of the Leu309 site of the PP2A catalytic subunit (PP2Ac) may decrease the interaction of PP2Ac with PP2A Bα and reduce the level of PP2ABαC holoenzyme, which is the main form of PP2A for tau dephosphorylation.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sontag et al. (2004a, 2004b)
Not checked in the free run.
May combine two claims.
Interpretationown dataIncreased CIP2A expression promoted AD pathogenesis indicated by tau phosphorylation, Aβ over-production, synapse loss, and cognitive impairments.
“Using the brain tissues, we showed that increased CIP2A expression promoted AD pathogenesis indicated by tau phosphorylation, Aβ over-production, synapse loss, and cognitive impairments.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationPP2A participates in dephosphorylation of a large number of substrates in addition to tau and APP, such as p53, MEK, ERK, and Akt.
“Furthermore, PP2A participates in dephosphorylation of a large number of substrates in addition to tau and APP, such as p53, mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and Akt (Dennis et al., 2014; Junttila et al., 2007; Ugi et al., 2002).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationThe inhibitory effect of CIP2A on PP2A is highly specific; PP2A is the only target of CIP2A.
“First, the inhibitory effect of CIP2A on PP2A is highly specific. A large number of studies especially on cancer have shown that PP2A is the only target of CIP2A (Junttila et al., 2007; Soo Hoo et al., 2002).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationY307 phosphorylation of PP2A was increased in AD and contributed to PP2A inhibition.
“We have reported that Y307 phosphorylation of PP2A was increased in AD and contributed to PP2A inhibition (Liu et al., 2008).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Liu et al., 2008 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe first crystal structure of CIP2A was recently published and revealed potential druggable structures.
“Third, the first crystal structure of CIP2A was recently published and revealed potential druggable structures (Wang et al., 2017).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wang et al., 2017 source
Not checked in the free run.
May combine two claims.
PremisecitationPP2A suppression induces APP phosphorylation at T668, leading to enhanced β-secretase processing of APP.
“PP2A suppression also induces APP phosphorylation at the T668 site, leading to enhanced β-secretase processing of APP (Sontag et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sontag et al., 2007 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDrugs have been identified aiming to inhibit CIP2A in cancer therapy.
“Actually, drugs have been identified aiming to inhibit CIP2A in cancer therapy (De et al., 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites De et al., 2014
Not checked in the free run.
May combine two claims.
PremisecitationIn tumor tissues, CIP2A inhibits the dephosphorylation of c-Myc at Ser62 by PP2A, protecting c-Myc from degradation, without affecting p53 and MEK phosphorylation.
“For example, in tumor tissues, CIP2A inhibits the dephosphorylation of c-Myc at the Ser62 site by PP2A, and thus protects c-Myc from degradation, without affecting p53 and MEK phosphorylation (Junttila et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Junttila et al., 2007 source
Not checked in the free run.
The paper relies on this without support.
The molecular mechanisms underlying PP2A inhibition in AD remain unclear.
“However, even though modulation of PP2A activity in transgenic mouse models (Nicholls et al., 2016) further supports the causative role for PP2A inhibition in AD pathologies, the molecular mechanisms underlying PP2A inhibition in AD remain less clear.”
The paper relies on this without support.
CIP2A has not been implicated in any neurodegenerative disorder.
“However, thus far CIP2A has not been implicated in any neurodegenerative disorder.”
The paper relies on this without support.
The endogenous pathophysiological mechanisms that inhibit PP2A activity in human AD have not been resolved.
“However, the endogenous pathophysiological mechanisms that inhibit PP2A activity in human AD have not been resolved.”
The paper relies on this without support.
Aβ toxicity is the central and initial event in AD development.
“Aβ toxicity is regarded as the central and initial event in AD development.”
The paper relies on this without support.
Phosphorylation sites S396 and S404 of tau are typical sites involved in AD.
“both typical phosphorylation sites involved in AD”
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?
CIP2A is strongly implicated in Alzheimer's disease via regulation of both Tau and APP.
“As CIP2A is also strongly implicated in Alzheimer´s disease via regulation of both Tau and APP32,58”
From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [32]
Cites
Amyloid 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 · see citing works
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× · see citing works
“Its neuropathology is defined by extracellular accumulation of amyloid-β peptides into amyloid plaques and intraneuronal fibrillar aggregates of hyper- and abnormally phosphorylated tau proteins (Masters et al., 1985; Grundke-Iqbal et al., 1986).”
BackgroundReducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model
Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., Gerstein, H., Yu, G.-Q., & Mucke, L. (2007) · Science · doi:10.1126/science.1141736 · Cited by 1,892 · see citing works
Janssens, V., & Goris, J. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3530417 · Cited by 1,890 · see citing works
Gene regulation and DNA damage in the ageing human brain
Lu, T., Pan, Y., Kao, S.-Y., Li, C., Kohane, I., Chan, J., & Yankner, B. A. (2004) · Nature · doi:10.1038/nature02661 · Cited by 1,874 · cited 1× · see citing works
“With DNA damage as a common event in aging (Lu et al., 2004), increased CIP2A expression is very possibly induced during the aging process.”
BackgroundMicrotubule-associated protein tau. A component of Alzheimer paired helical filaments.
Grundke, I., Iqbal, K., Quinlan, M., Tung, Y. C., Zaidi, M. S., & Wisniewski, H. M. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)38495-8 · Cited by 1,780 · cited 1× · see citing works
“Its neuropathology is defined by extracellular accumulation of amyloid-β peptides into amyloid plaques and intraneuronal fibrillar aggregates of hyper- and abnormally phosphorylated tau proteins (Masters et al., 1985; Grundke-Iqbal et al., 1986).”
BackgroundEnhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP
Lewis, J., Dickson, D. W., Lin, W.-L., Chisholm, L., Corral, A., Jones, G., Yen, S.-H., Sahara, N., Skipper, L., Yager, D., et al. (2001) · Science · doi:10.1126/science.1058189 · Cited by 1,611 · cited 1× · see citing works
“Mice expressing mutated human APP and mutated human tau develop several-fold increased neurofibrillary tangles, compared with mice expressing only mutated human tau (Lewis et al., 2001).”
BackgroundFormation of Neurofibrillary Tangles in P301L Tau Transgenic Mice Induced by Aβ42 Fibrils
Götz, J., Chen, F., van Dorpe, J., & Nitsch, R. M. (2001) · Science · doi:10.1126/science.1062097 · Cited by 1,526 · cited 1× · see citing works
“Aβ induces tau filament formation in mouse brain (Götz et al., 2001).”
BackgroundJanssens, V., & Goris, J. (2001) · Biochemical Journal · doi:10.1042/bj3530417 · Cited by 1,392 · see citing works
Amyloid-β and tau — a toxic pas de deux in Alzheimer's disease
Ittner, L. M., & Götz, J. (2010) · Nature reviews. Neuroscience · doi:10.1038/nrn2967 · Cited by 1,357 · see citing works
Tau is essential to β-amyloid-induced neurotoxicity
Rapoport, M., Dawson, H. N., Binder, L. I., Vitek, M. P., & Ferreira, A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.092136199 · Cited by 807 · see citing works
Tau and neurodegenerative disease: the story so far
Iqbal, K., Liu, F., & Gong, C.-X. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.225 · Cited by 806 · cited 1× · see citing works
“PP2A inactivation is regarded as the most important molecular event that causes abnormal tau hyperphosphorylation in the AD brain (Iqbal et al., 2016).”
BackgroundOddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H., & LaFerla, F. M. (2004) · Neuron · doi:10.1016/j.neuron.2004.07.003 · Cited by 780 · see citing works
Liu, F., Grundke‐Iqbal, I., Iqbal, K., & Gong, C. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04391.x · Cited by 759 · cited 1× · see citing works
“In vitro analysis of the dephosphorylation ability of different phosphatases toward tau showed that PP2A contributed 71% of the dephosphorylation of human hyperphosphorylated tau isolated from AD patient brains (Liu et al., 2005).”
CIP2A inhibits PP2A in human malignancies
Junttila, M. R., Puustinen, P., Niemelä, M., Ahola, R., Arnold, H., Böttzauw, T., Ala-aho, R., Nielsen, C., Ivaska, J., Taya, Y., et al. (2007) · Cell · doi:10.1016/j.cell.2007.04.044 · Cited by 677 · cited 6× · see citing works
“For example, in tumor tissues, CIP2A inhibits the dephosphorylation of c-Myc at the Ser62 site by PP2A, and thus protects c-Myc from degradation, without affecting p53 and MEK phosphorylation (Junttila et al., 2007).”
BackgroundInfluentialSelf-citationHutchinson, E. (2011) · Nature reviews. Neuroscience · doi:10.1038/nrn2985 · Cited by 534 · see citing works
Phosphoprotein Phosphatase Activities in Alzheimer Disease Brain
Gong, C., Singh, T. J., Grundke‐Iqbal, I., & Iqbal, K. (1993) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1993.tb03603.x · Cited by 527 · cited 1× · see citing works
“In Alzheimer’s disease (AD) patient brains, PP2A activities were decreased (Gong et al., 1993, 1995).”
Suberbielle, E., Sanchez, P. E., Kravitz, A. V., Wang, X., Ho, K., Eilertson, K., Devidze, N., Kreitzer, A. C., & Mucke, L. (2013) · Nature Neuroscience · doi:10.1038/nn.3356 · Cited by 487 · cited 2× · see citing works
“In AD neurons, oxidative DNA damage signaling is induced by exposure of cells to Aβ (Suberbielle et al., 2013; Wu et al., 2014; Yan et al., 2014).”
BackgroundSelf-citationPhosphatase Activity Toward Abnormally Phosphorylated τ: Decrease in Alzheimer Disease Brain
Gong, C., Shaikh, S., Wang, J., Zaidi, T., Grundke, I., & Iqbal, K. (1995) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1995.65020732.x · Cited by 440 · see citing works
Self-citationTau association with synaptic vesicles causes presynaptic dysfunction
Zhou, L., McInnes, J., Wierda, K., Holt, M., Herrmann, A. G., Jackson, R. J., Wang, Y.-C., Swerts, J., Beyens, J., Miskiewicz, K., et al. (2017) · Nature Communications · doi:10.1038/ncomms15295 · Cited by 434 · see citing works
Gong, C.-X., Lidsky, T., Wegiel, J., Zuck, L., Grundke-Iqbal, I., & Iqbal, K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.8.5535 · Cited by 405 · cited 1× · see citing works
“Inhibition of PP2A in cultured brain slices and rat brains induced tau hyperphosphorylation at multiple sites known to be related to AD (Gong et al., 2000; Sun et al., 2003).”
BackgroundOomen, C. A., Soeters, H., Audureau, N., Vermunt, L., van Hasselt, F. N., Manders, E. M. M., Joëls, M., Lucassen, P. J., & Krugers, H. J. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0247-10.2010 · Cited by 352 · cited 1× · see citing works
“Of the latter, dendritic spines are highly dynamic and can respond to external stimuli with structural remodeling (Oomen et al., 2010).”
Zempel, H., Luedtke, J., Kumar, Y., Biernat, J., Dawson, H., Mandelkow, E., & Mandelkow, E. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.207 · Cited by 283 · cited 1× · see citing works
“In primary neurons, we further observed that CIP2A promoted tau translocalization to dendrites and spines, which is considered to be the key event mediating the synaptic toxicity of tau (Pooler et al., 2014; Zempel et al., 2013).”
BackgroundDephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B
Wang, J.-Z., Gong, C.-X., Zaidi, T., Grundke-Iqbal, I., & Iqbal, K. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.9.4854 · Cited by 269 · cited 1× · see citing works
“Incubation of PP2A with hyperphosphorylated tau resulted in tau dephosphorylation and restoration of tau function in promoting microtubule assembly (Wang et al., 1995).”
Self-citationYan, S., Sorrell, M., & Berman, Z. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1666-4 · Cited by 247 · cited 2× · see citing works
“In AD neurons, oxidative DNA damage signaling is induced by exposure of cells to Aβ (Suberbielle et al., 2013; Wu et al., 2014; Yan et al., 2014).”
BackgroundSontag, E., Luangpirom, A., Hladik, C., Mudrak, I., Ogris, E., Speciale, S., & White, C. L. (2004) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/63.4.287 · Cited by 228 · see citing works
Sontag, E., Nunbhakdi-Craig, V., Sontag, J.-M., Diaz-Arrastia, R., Ogris, E., Dayal, S., Lentz, S. R., Arning, E., & Bottiglieri, T. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.3316-06.2007 · Cited by 225 · cited 2× · see citing works
“PP2A suppression also induces APP phosphorylation at the T668 site, leading to enhanced β-secretase processing of APP (Sontag et al., 2007).”
BackgroundUp-regulation of inhibitors of protein phosphatase-2A in Alzheimer’s disease
Tanimukai, H., Grundke-Iqbal, I., & Iqbal, K. (2005) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)62486-8 · Cited by 220 · cited 1× · see citing works
“In addition, an altered cellular location of endogenous PP2A inhibitors was reported to induce PP2A inactivation in cytoplasm (Tanimukai et al., 2005).”
BackgroundA role for tau at the synapse in Alzheimer’s disease pathogenesis
Pooler, A. M., Noble, W., & Hanger, D. P. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.09.018 · Cited by 203 · see citing works
Hoo, L. S., Zhang, J. Y., & Chan, E. K. (2002) · Oncogene · doi:10.1038/sj.onc.1205625 · Cited by 201 · see citing works
Sontag, E., Hladik, C. L., Montgomery, L. G., Luangpirom, A., Mudrak, I., Ogris, E., & White, C. L. (2004) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/63.10.1080 · Cited by 191 · see citing works
Sun, L., Liu, S. Y., Zhou, X. W., Wang, X. C., Liu, R., Wang, Q., & Wang, J. Z. (2003) · Neuroscience · doi:10.1016/s0306-4522(02)00697-8 · Cited by 168 · cited 1× · see citing works
“Inhibition of PP2A in cultured brain slices and rat brains induced tau hyperphosphorylation at multiple sites known to be related to AD (Gong et al., 2000; Sun et al., 2003).”
BackgroundSelf-citationREDD1 enhances protein phosphatase 2A-mediated dephosphorylation of Akt to repress mTORC1 signaling
Dennis, M. D., Coleman, C. S., Berg, A., Jefferson, L. S., & Kimball, S. R. (2014) · Science Signaling · doi:10.1126/scisignal.2005103 · Cited by 159 · cited 2× · see citing works
“REDD1 enhances protein phosphatase 2A-mediated dephosphorylation of Akt to repress mTORC1 signaling.”
BackgroundKhanna, A., Pimanda, J. E., & Westermarck, J. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-1994 · Cited by 154 · cited 3× · see citing works
“Cancerous Inhibitor of PP2A (CIP2A) has been shown to be upregulated in a variety of peripheral tumors, leading to an inhibition of PP2A activity (Junttila et al., 2007; Soo Hoo et al., 2002; Khanna et al., 2013a).”
Self-citationLaine, A., Sihto, H., Come, C., Rosenfeldt, M. T., Zwolinska, A., Niemelä, M., Khanna, A., Chan, E. K., Kähäri, V.-M., Kellokumpu-Lehtinen, P.-L., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0292 · Cited by 130 · cited 2× · see citing works
“The robust tumor-promoting effects of CIP2A overexpression has been linked to selective regulation of well-established cancer drivers such as MYC and E2F1 (Junttila et al., 2007; Laine et al., 2013).”
BackgroundSelf-citationPhosphorylated PP2A (tyrosine 307) is associated with Alzheimer neurofibrillary pathology
Liu, R., Zhou, X. ‐., Tanila, H., Bjorkdahl, C., Wang, J. ‐., Guan, Z. ‐., Cao, Y., Gustafsson, J. ‐., Winblad, B., & Pei, J. ‐. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00249.x · Cited by 125 · cited 1× · see citing works
“We have reported that Y307 phosphorylation of PP2A was increased in AD and contributed to PP2A inhibition (Liu et al., 2008).”
Self-citationOncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56
Wang, J., Okkeri, J., Pavic, K., Wang, Z., Kauko, O., Halonen, T., Sarek, G., Ojala, P. M., Rao, Z., Xu, W., et al. (2017) · The EMBO Reports · doi:10.15252/embr.201642788 · Cited by 95 · cited 1× · see citing works
“Third, the first crystal structure of CIP2A was recently published and revealed potential druggable structures (Wang et al., 2017).”
BackgroundSelf-citationUgi, S., Imamura, T., Ricketts, W., & Olefsky, J. M. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.7.2375-2387.2002 · Cited by 95 · cited 2× · see citing works
“REDD1 enhances protein phosphatase 2A-mediated dephosphorylation of Akt to repress mTORC1 signaling.”
BackgroundDe, P. K., Carlson, J. H., Leyland-Jones, B. R., & Dey, N. (2014) · Oncotarget · doi:10.18632/oncotarget.2127 · Cited by 72 · cited 1× · see citing works
“Actually, drugs have been identified aiming to inhibit CIP2A in cancer therapy (De et al., 2014).”
BackgroundSun, X., Tuo, Q., Liuyang, Z., Xie, A., Feng, X.-L., Yan, X., Qiu, M., Shen, L., Wang, X.-L., Cao, F.-Y., et al. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.329 · Cited by 71 · see citing works
Self-citationNicholls, R. E., Sontag, J.-M., Zhang, H., Staniszewski, A., Yan, S., Kim, C. Y., Yim, M., Woodruff, C. M., Arning, E., Wasek, B., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521018113 · Cited by 56 · cited 2× · see citing works
“However, even though modulation of PP2A activity in transgenic mouse models (Nicholls et al., 2016) further supports the causative role Shentu et al.”
NAD attenuates oxidative DNA damages induced by amyloid beta-peptide in primary rat cortical neurons
Wu, M.-H., Yin, J., Hwang, C.-S., Tang, C.-M., & Yang, D. (2014) · Free Radical Research · doi:10.3109/10715762.2014.907889 · Cited by 46 · cited 2× · see citing works
“In AD neurons, oxidative DNA damage signaling is induced by exposure of cells to Aβ (Suberbielle et al., 2013; Wu et al., 2014; Yan et al., 2014).”
BackgroundChk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells
Khanna, A., Kauko, O., Böckelman, C., Laine, A., Schreck, I., Partanen, J. I., Szwajda, A., Bormann, S., Bilgen, T., Helenius, M., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-1002 · Cited by 45 · see citing works
Self-citationCIP2A increases self-renewal and is linked to Myc in neural progenitor cells
Kerosuo, L., Fox, H., Perälä, N., Ahlqvist, K., Suomalainen, A., Westermarck, J., Sariola, H., & Wartiovaara, K. (2010) · Differentiation · doi:10.1016/j.diff.2010.04.003 · Cited by 35 · cited 2× · see citing works
“Interestingly, in addition to the peripheral tissues, CIP2A is also expressed in normal adult human and mouse brains, especially in olfactory bulb and hippocampus (Kerosuo et al., 2010).”
BackgroundSelf-citationExpression and biological role of CIP2A in human astrocytoma
Yi, F., Ni, W., Liu, W., BAI, J., & Li, W. (2013) · Molecular Medicine Reports · doi:10.3892/mmr.2013.1357 · Cited by 20 · cited 1× · see citing works
“Another study suggested a role of CIP2A in the development of astrocytoma (Yi et al., 2013).”
BackgroundLong-term Helicobacter pylori infection does not induce tauopathy and memory impairment in SD rats
Zhou, H., Guo, Y. J., Li, X., Liuyang, Z.-Y., Shentu, Y., Jing, X., Liang, J., Zhou, X., Wang, X., Wang, J., et al. (2017) · Current Medical Science · doi:10.1007/s11596-017-1813-x · Cited by 6 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
The complexity of tau in Alzheimer’s disease
Naseri, N. N., Wang, H., Guo, J. D., Sharma, M., & Luo, W. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.04.022 · Cited by 374 · see citing works
Liu, Q., Sun, Y.-M., Huang, H., Chen, C., Wan, J., Ma, L., Sun, Y.-Y., Miao, H., & Wu, Y. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02089-z · Cited by 170 · see citing works
Basheer, N., Smolek, T., Hassan, I., Liu, F., Iqbal, K., Zilka, N., & Novak, P. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02113-z · Cited by 159 · see citing works
Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis
Sanchez-Varo, R. M., Mejias‐Ortega, M., Fernandez-Valenzuela, J. J., Nuñez‐Diaz, C., Cáceres-Palomo, L., Vegas‐Gomez, L., Sánchez‐Mejías, E., Trujillo‐Estrada, L., García‐León, J. A., Moreno‐González, I., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105404 · Cited by 130 · see citing works
Phosphorylation Signaling in APP Processing in Alzheimer’s Disease
Zhang, T., Chen, D., & Lee, T. H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms21010209 · Cited by 114 · see citing works
Pan, J., Zhou, L., Zhang, C., Xu, Q., & Sun, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01038-3 · Cited by 115 · see citing works
Kumar, V., Kim, S.-H., & Bishayee, K. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179540 · Cited by 115 · see citing works
“Furthermore, a recent study reported the overexpression of a cancerous inhibitor of PP2A (CIP2A; an endogenous inhibitor of PP2A) in the AD brain that allows tau phosphorylation and drives the AD pathogenesis [97].”
BackgroundJayaraj, R. L., Azimullah, S., & Beiram, R. (2019) · Saudi Journal of Biological Sciences · doi:10.1016/j.sjbs.2019.12.028 · Cited by 105 · see citing works
Wang, L., Bharti, Kumar, R., Pavlov, P. F., & Winblad, B. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112915 · Cited by 92 · see citing works
Huang, S., Dong, W., Lin, X., Xu, K., Li, K., Xiong, S., Wang, Z., Nie, X., & Bian, J.-S. (2024) · Immunity · doi:10.1016/j.immuni.2024.01.018 · Cited by 82 · see citing works
Kauko, O., Imanishi, S. Y., Kulesskiy, E., Yetukuri, L., Laajala, T. D., Sharma, M., Pavic, K., Aakula, A., Rupp, C., Jumppanen, M., et al. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.011265 · Cited by 65 · see citing works
“However, despite its critical role in cancer, and in many other diseases (20), the effects of endogenous PP2A-modulating mechanisms on phospho-signaling have not yet been systematically analyzed.”
BackgroundSelf-citationTargeting 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 69 · see citing works
“Moreover, silencing I2PP2A or inhibiting CIP2A expression could decrease hyperphosphorylation of tau and improve memory deficits (Liu et al., 2013; Zhang et al., 2014a; Shentu et al., 2018).”
Zhang, Q., Xia, Y., Luo, H., Huang, S., Wang, Y., Shentu, Y., Mahaman, Y. A. R., Huang, F., Ke, D., Wang, Q., et al. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00437 · Cited by 61 · see citing works
Self-citationJeong, H. S., Song, I., Chung, Y., Park, J., Na, S., Im, J. J., Bikson, M., Lee, W., & Yoo, S. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12020250 · Cited by 60 · see citing works
“Decreased dendritic spine density and impaired maintenance of long-term potentiation have been reported in the hippocampus of AD animal models [27,28].”
BackgroundCodonopsis pilosula polysaccharide attenuates Aβ toxicity and cognitive defects in APP/PS1 mice
Wan, L., Zhang, Q., Luo, H., Xu, Z., Huang, S., Yang, F., Liu, Y., Mahaman, Y. A. R., Ke, D., Wang, Q., et al. (2020) · Aging · doi:10.18632/aging.103445 · Cited by 59 · see citing works
“Novel object recognition (NOR) tests were performed referring to Shentu’s study [48].”
MethodSelf-citationHuang, X., Zheng, H., Lin, Z., Wang, K., Liu, X., Zhou, W., Meng, L., Huang, J., Yuan, K., & Niu, L. (2019) · IEEE Transactions on Ultrasonics Ferroelectrics and Frequency Control · doi:10.1109/tuffc.2019.2903896 · Cited by 57 · see citing works
“It has been demonstrated that the density of dendritic spines is reduced, and the maintenance of longterm potentiation is impaired in the hippocampus of a model of Alzheimer’s disease [5], [6].”
BackgroundWan, H.-L., Hong, X.-Y., Zhao, Z.-H., Li, T., Zhang, B.-G., Liu, Q., Wang, Q., Zhao, S., Wang, J.-Z., Shen, X., et al. (2021) · Theranostics · doi:10.7150/thno.56541 · Cited by 49 · see citing works
“The recognition index was calculated by TC/ (TA + TC) [52].”
MethodSelf-citationWei, H., Zhang, H., Wang, X., Xie, J., An, D., Wan, L., Wang, J., Zeng, Y., Shu, X., Westermarck, J. K., et al. (2020) · Neurotherapeutics · doi:10.1007/s13311-020-00841-6 · Cited by 54 · see citing works
Self-citationFujiki, H., Sueoka, E., Watanabe, T., & Suganuma, M. (2018) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-018-2765-7 · Cited by 49 · see citing works
Protein Phosphatase 2A (PP2A) mutations in brain function, development, and neurologic disease
Verbinnen, I., Vaneynde, P., Reynhout, S., Lenaerts, L., Derua, R., Houge, G., & Janssens, V. (2021) · Biochemical Society Transactions · doi:10.1042/bst20201313 · Cited by 48 · see citing works
The multifaceted role of WNT signaling in Alzheimer’s disease onset and age-related progression.
Kostes, W. W., & Brafman, D. A. (2023) · Cells · doi:10.3390/cells12081204 · Cited by 43 · see citing works
Sex-Specific Regulation of Fear Memory by Targeted Epigenetic Editing of Cdk5
Sase, A., Lombroso, S. I., Santhumayor, B. A., Wood, R. R., Lim, C. J., Neve, R. L., & Heller, E. A. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.11.022 · Cited by 40 · see citing works
Dendritic/Post-synaptic Tau and Early Pathology of Alzheimer’s Disease
Yin, X., Zhao, C., Qiu, Y., Zhou, Z., Bao, J., & Qian, W. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.671779 · Cited by 39 · see citing works
Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A
Pavic, K., Gupta, N., Omella, J. D., Derua, R., Aakula, A., Huhtaniemi, R., Määttä, J. A., Höfflin, N., Okkeri, J., Wang, Z., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36693-9 · Cited by 36 · see citing works
“The data show that the CIP2A(1-560) residues cross-linked to B56α are located primarily in the N-terminal head domain (K18, K21, E23, E34, K40) with an additional residue at the C-terminus (K490) (Fig.”
BackgroundMethodInfluentialSelf-citationYe, J., Yin, Y., Liu, H., Fang, L., Tao, X., Wei, L., Zuo, Y., Yin, Y., Ke, D., & Wang, J. (2019) · Aging Cell · doi:10.1111/acel.13055 · Cited by 36 · see citing works
“Tau is a axonallocated microtubuleassociated protein involving in microtubule assemble and stabilization; however, ab normal dendritic translocation of tau proteins induces the den dritic complex loss and synaptic neurodegeneration (Shentu et al., 2018).”
BackgroundSelf-citationChen, X., Dong, G., & Wang, L. (2020) · Brain and Behavior · doi:10.1002/brb3.1740 · Cited by 36 · see citing works
“Each mouse was habituate in the box for two consecutive days without objects according to Shentu's study (Shentu et al., 2018).”
MethodMerisaari, J., Denisova, O. V., Doroszko, M., Joncour, V. L., Johansson, P., Leenders, W. P. J., Kastrinsky, D. B., Zaware, N., Narla, G., Laakkonen, P. M., et al. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa002 · Cited by 33 · see citing works
“Suppression of PP2A activity is also one of the pathogenic mechanisms underlying several neurodegenerative diseases, including Alzheimer’s (Shentu et al. , 2018) and Parkinson’s diseases; thus, our data demonstrating BBB penetration and in vivo therapeutic effects of SMAPs in the intracranial model…”
Self-citationShastri, D., Raj, V., & Lee, S.-K. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102379 · Cited by 34 · see citing works
Kumar, D., Sharma, A., & Sharma, L. K. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200203101828 · Cited by 33 · see citing works
TREM2 and Microglia Contribute to the Synaptic Plasticity: from Physiology to Pathology
Yu, C.-J., Wang, M., Ruiyang, L., Wei, T., Yang, H.-C., Yin, Y., Mi, Y., Qin, Q., & Tang, Y. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-03100-1 · Cited by 33 · see citing works
“Other irregular forms of tau protein, such as mutated, truncated, and acetylated forms, may also disrupt synaptic structure or function [47, 49, 50].”
BackgroundZhao, H., Cui, S., Yu, Q., Liu, Y., Cui, X., Hu, X., Kurban, N., Li, M.-Y., Li, Z., Xu, J., et al. (2020) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2020.113725 · Cited by 32 · see citing works
Ye, J.-W., Yin, Y., Yin, Y.-L., Zhang, H.-Q., Wan, H.-L., Wang, L., Zuo, Y., Gao, D., Li, M.-Z., Li, J., et al. (2020) · Aging Cell · doi:10.1111/acel.13209 · Cited by 22 · see citing works
“Decreased PP2A activity has been evidenced in the frontal and temporal cortices of AD patients (Sontag et al., 2004), which promotes tau hyperphosphorylation, and subsequent NFTs formation and synaptic degeneration (Shentu et al., 2018; Sun et al., 2012).”
BackgroundSelf-citationHu, W., Wang, Z., Zhang, H., Mahaman, Y. A. R., Huang, F., Meng, D., Zhou, Y., Wang, S., Jiang, N., Xiong, J., et al. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01204-z · Cited by 27 · see citing works
“Consistent with our previous results from cancer cells [5], the Chk1 phosphorylation on serine 345 was highly correlated with levels of DNA damage and CIP2A expression (Fig.”
BackgroundResultInfluentialSelf-citationKIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss
Kauwe, G., Pareja-Navarro, K. A., Yao, L., Chen, J. H., Wong, I., Saloner, R., Cifuentes, H., Nana, A. L., Shah, S., Li, Y., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci169064 · Cited by 27 · see citing works
“…underlies the formation of new memories, and LTP is inhibited by tau with mutations that cause familial frontotemporal dementia(FTD) (8, 10, 11), as well as several AD-associated pathogenic forms of tau including hyperacetylated tau (9), hyperphosphorylated tau (12, 13), and tau oligomers (14, 15).”
Identification of new BACE1 inhibitors for treating Alzheimer’s disease
Kushwaha, P., Singh, V., Somvanshi, P., Bhardwaj, T., Barreto, G. E., Ashraf, G. M., Mishra, B. N., Chundawat, R. S., & Haque, S. (2021) · Journal of Molecular Modeling · doi:10.1007/s00894-021-04679-3 · Cited by 25 · see citing works
“The reported causes of increased amyloid beta overproduction are enhanced levels of intracellular iron, increased oxidative stress, inactivation of protein phosphatase 2A (PP2A), and inhibitory effects of Zn ions on α-secretase [12, 13].”
BackgroundJia, Y., Wang, X., Chen, Y., Qiu, W., Ge, W., & Ma, C. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02356-3 · Cited by 24 · see citing works
“Learning and memory deficits, tau hyperphosphorylation and Aβ overproduction were identified in the brain of transgenic cancerous inhibitor of PP2A (CIP2A) mice[105].”
BackgroundSelf-citationPP2A and Its Inhibitors in Helper T-Cell Differentiation and Autoimmunity
Khan, M. M., Ullah, U., Khan, M. H., & Lahesmaa, R. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.786857 · Cited by 25 · see citing works
“PP2A inhibition by CIP2A overexpression in Alzheimer’s disease (43) leads to the accumulation of hyperphosphorylated tau protein aggregates and Alzheimer’s development.”
BackgroundTargeting of PP2 A/GSK3β/PTEN Axis in Alzheimer Disease: The Mooting Evidence, Divine, and Devil
Alqahtani, S. M., Al-Kuraishy, H. M., Al-Gareeb, A. I., Abdel‐Fattah, M. M., Alsaiari, A. A., Alruwaili, M., Papadakis, M., Alexiou, A. T., & Batiha, G. E. (2025) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-025-01554-0 · Cited by 26 · see citing works
“Deficits in PP2 A activity are harmonized with the reported down‑regulation of PP2 A catalytic C subunit at the gene, mRNA, and protein expression levels in AD (Shentu et al. 2018).”
Meng, D., Yang, M., Hu, L., Liu, T., Zhang, H., Sun, X., Wang, X., Chen, Y., Jin, Y. T., & Liu, R. (2022) · Journal of Neurochemistry · doi:10.1111/jnc.15701 · Cited by 25 · see citing works
Self-citationVitamin D Attenuates Alzheimer-like Pathology Induced by Okadaic Acid
Pan, Y., Zhang, Y., Liu, N., Lu, W., Yang, J., Li, Y., Liu, Z., Wei, Y., Lou, Y., & Kong, J. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00812 · Cited by 21 · see citing works
Zhou, Y., Yang, D., Chen, H., Zheng, C., Jiang, H., Liu, X., Huang, X., Ye, S., Song, S., Jiang, N., et al. (2020) · The FASEB Journal · doi:10.1096/fj.202001499r · Cited by 20 · see citing works
“Novel objective recognition test Novel object recognition (NOR) tests were performed in a 50 cm × 50 cm × 50 cm white plastic box referring to Shentu's study (Shentu et al, 2018).”
Self-citationCIP2A Constrains Th17 Differentiation by Modulating STAT3 Signaling
Khan, M. M., Ullah, U., Khan, M. H., Kong, L., Moulder, R., Välikangas, T., Bhosale, S. D., Komsi, E., Rasool, O., Chen, Z. J., et al. (2020) · iScience · doi:10.1016/j.isci.2020.100947 · Cited by 20 · see citing works
Self-citationZhou, Y., Liu, X., Ma, S., Zhang, N., Yang, D., Wang, L., Ye, S., Zhang, Q., Ruan, J., Ma, J., et al. (2022) · The FASEB Journal · doi:10.1096/fj.202101625r · Cited by 18 · see citing works
Self-citationLiu, Y., Liu, Q., Wang, H., Qiu, Y., Lin, J.-T., Wu, W.-F., Wang, N., Dong, W., Wan, J., Chen, C., et al. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14410 · Cited by 18 · see citing works
The regulatory role of Pin1 in neuronal death
Xiong, K., Wang, S., & Hu, X. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.341043 · Cited by 18 · see citing works
“A large body of evidence now suggests that interaction between Aβ and Tau could enhance the process of AD (Selkoe and Hardy, 2016; Shentu et al., 2018).”
BackgroundAlzheimer’s disease basics: we all should know
Das, S. K. (2025) · Neurological Research · doi:10.1080/01616412.2025.2529560 · Cited by 19 · see citing works
“According to research, hyperphosphorylated dendritic tau is a major factor in dendritic loss, abnormal postsynaptic activity, and cognitive dysfunction in AD [107–109].”
Gu, L., Cai, N., Li, M., Bi, D., Yao, L., Fang, W., Wu, Y. L., Hu, Z., Liu, Q., Lin, Z., et al. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.892558 · Cited by 15 · see citing works
“Previous studies have proven that the inhibition of PP2A activity results in Tau hyperphosphorylation and spatial memory deficiency (37), which indicates that PP2A might be a therapeutic target for AD.”
BackgroundShentu, Y., Hu, W., Liang, J., Liuyang, Z., Wei, H., Qun, W., Wang, X., Wang, J., Westermarck, J. K., & Liu, R. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190830113420 · Cited by 15 · see citing works
Self-citationLi, L.-J., Sun, X., Huang, Y., Lü, S., Xu, Y., Yang, J., Xie, X.-X., Zhu, J., Niu, X., Wang, D., et al. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00427-8 · Cited by 14 · see citing works
“Furthermore, cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous PP2A inhibitor [36] that is over-expressed in AD brain [37], was significantly increased in DNase II-deficient neurons (Fig.”
BackgroundSelf-citationApoE-calypse tau: ApoE–tau synergy in Alzheimer’s disease
Lennol, M. P., Bordier, C., Kamelher, L., Ulrich, J. D., Holtzman, D. M., & Gratuze, M. (2025) · The Journal of Experimental Medicine · doi:10.1084/jem.20250965 · Cited by 14 · see citing works
Fan, Y., Guo, C., Zhao, L., Ge, R., Pang, Z., He, D., Ren, H., Wu, T., Zhang, Y., & Wang, Z. (2023) · British Journal of Pharmacology · doi:10.1111/bph.16161 · Cited by 14 · see citing works
“In this study, astrocytic Lf overexpression inhibited the neuronal APP phosphorylation at Thr668, thereby diminishing A β burden in APP/PS1 mice.”
BackgroundInfluentialZhang, W., Ou, H., Zhang, B., Zheng, M., Yan, L., Chen, Y., So, K., & Zhang, L. (2021) · Neuroscience Bulletin · doi:10.1007/s12264-021-00766-w · Cited by 13 · see citing works
“level [5], and PP2A inhibition thus results in tau hyperphosphorylation, which is one of the core pathological features underlying neurodegenerative disorders.”
BackgroundInfluentialMicroglia activation mediates circadian rhythm disruption-induced cognitive impairment in mice
Meng, D., Yang, M., Zhang, H., Zhang, L., Song, H., Liu, Y., Zeng, Y., Yang, B. K., Wang, X., Chen, Y., et al. (2023) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2023.578102 · Cited by 12 · see citing works
Self-citationHayne, M. R., & DiAntonio, A. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105586 · Cited by 12 · see citing works
Tau Acts in Concert With Kinase/Phosphatase Underlying Synaptic Dysfunction
Fan, X., Xia, L., Zhou, Z., Qiu, Y., Zhao, C., Yin, X., & Qian, W. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.908881 · Cited by 11 · see citing works
Discovering new peripheral plasma biomarkers to identify cognitive decline in type 2 diabetes
Yu, H., Gao, Y., He, T., Li, M., Zhang, Y., Zheng, J., Jiang, B., Chen, C., Ke, D., Liu, Y., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.818141 · Cited by 10 · see citing works
“As an endogenous PP2A inhibitor, CIP2A promotes tau and APP phosphorylation and Aβ production (Shentu et al., 2018).”
BackgroundSelf-citationGuo, H., Ou, H., Yu, J., Rosa, J. M., Formolo, D. A., Cheng, T., Yau, S., & Tsang, H. W. H. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-00943 · Cited by 10 · see citing works
“Osmotin, and Os-pep, have beneficial effects on neurodegenerative diseases (Choi et al., 2016, 2018b; Amin et al., 2017; Shah et al., 2017; Yoon et al., 2018; Schön et al., 2019; Lee et al., 2021c; Ng et al., 2021).”
Speranza, L., Filiz, K. D., Goebel, S., Perrone‐Capano, C., Pulcrano, S., Volpicelli, F., & Francesconi, A. (2022) · Biomedicines · doi:10.3390/biomedicines10112692 · Cited by 10 · see citing works
Chaiwijit, P., Uppakara, K., Asavapanumas, N., & Saengsawang, W. (2023) · Biomedicines · doi:10.3390/biomedicines11041011 · Cited by 9 · see citing works
“Moreover, PP2A dysfunction has been linked to several pathological hallmarks of AD, including tau hyperphosphorylation, amyloidogenesis, and synaptic deficits [20,21].”
BackgroundZhu, L., Huang, Y., Jin, J., Zou, R., Zuo, R. M., Luo, Y. M., Song, Z., Dai, L., Zhang, M., Chen, Q., et al. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.11.015 · Cited by 8 · see citing works
Hu, W., Liuyang, Z., Tian, Y., Liang, J., Zhang, X., Zhang, H., Wang, G., Huo, Y., Shentu, Y., Wang, J., et al. (2022) · EMBO Reports · doi:10.15252/embr.202254911 · Cited by 8 · see citing works
“Further, CIP2A overexpression has been shown to promote Alzheimer’s disease (AD) development in mouse models (Shentu et al , 2018, 2019).”
Self-citationNeuschmid, S., Schallerer, C., Ehrlich, B. E., & McGuone, D. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26189245 · Cited by 7 · see citing works
“A β inhibits PP2A, amplifying cell injury [157].”
Xiao, X., Jiao, B., Liao, X., Zhang, W., Yuan, Z., Guo, L., Wang, X., Zhou, L., Liu, X., Yan, X., et al. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.584801 · Cited by 7 · see citing works
Self-citationArribas, R. L., Viejo, L., Bravo, I., Martinez-Castillo, M., Ramos, E., Romero, A., García‐Frutos, E. M., Janssens, V., Montiel, C., & Rı́os, C. D. L. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115245 · Cited by 7 · see citing works
Protein interactome of the Cancerous Inhibitor of protein phosphatase 2A (CIP2A) in Th17 cells
Khan, M. M., Välikangas, T., Khan, M. H., Moulder, R., Ullah, U., Bhosale, S. D., Komsi, E., Butt, U., Qiao, X., Westermarck, J. K., et al. (2020) · Current Research in Immunology · doi:10.1016/j.crimmu.2020.02.001 · Cited by 7 · see citing works
Self-citationAndo, S., Sakurai, M., Shibutani, S., Kimura, N., Shimozawa, N., Yasutomi, Y., Yabe, R., Ohama, T., & Sato, K. (2023) · The Journal of Biochemistry · doi:10.1093/jb/mvad006 · Cited by 6 · see citing works
Advances in Alzheimer’s disease: mechanistic insights and therapeutic targets
Jia, Y.-J., Ge, Y., Li, B., Yang, Y., Chen, H., Liu, J., Guo, J., Yu, J., Ye, K., Wang, J., et al. (2026) · Science China Life Sciences · doi:10.1007/s11427-025-2991-7 · Cited by 5 · see citing works
“Inhibiting PP2A leads to elevated tau phosphorylation, while activating PP2A reduces tau phosphorylation both in vitro and in vivo (Cheng et al., 2013; Liu et al., 2013a; Martin et al., 2013; Shentu et al., 2018; Wei et al., 2020).”
Self-citationAfsar, A., & Li, Z. (2024) · Biology · doi:10.3390/biology13030185 · Cited by 5 · see citing works
“The interaction between A β and tau is thought to exacerbate AD progression [325,331,332].”
BackgroundLiu, Z., Xi, Q., Hou, M., Zou, T., Liu, H., Zhou, X., Jin, L., Zhu, L., & Zhang, X. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2024.167228 · Cited by 5 · see citing works
SPIN90 Deficiency Ameliorates Amyloid β Accumulation by Regulating APP Trafficking in AD Model Mice
Oh, Y., Lee, W., Kim, S. H., Lee, S., Kim, B. C., Lee, K., Kim, S. H., & Song, W. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810563 · Cited by 4 · see citing works
Skóra, B., Piechowiak, T., & Szychowski, K. A. (2025) · Neuropharmacology · doi:10.1016/j.neuropharm.2025.110781 · Cited by 3 · see citing works
Ouyang, X., Zhao, Z., Hou, Y., Wang, S., Yang, Y., Hongzhuan, C. H. E. N., & Xu, J. (2026) · Phytomedicine · doi:10.1016/j.phymed.2026.157981 · Cited by 3 · see citing works
Guo, H., Ou, H. N., Yu, J., Luo, Z., Yau, S., & Tsang, H. W. H. (2026) · Aging Cell · doi:10.1111/acel.70447 · Cited by 3 · see citing works
“Significant reductions in PP2A mRNA (Vogelsberg-Ragaglia et al. 2001), PP2A protein (Guadagna et al. 2012; Jun et al. 2022; Zhao et al. 2003), and its activity (Shentu et al. 2018) in the brain tissue of AD and MCI patients underscores its role in AD pathogenesis.”
Ma, Y., Xu, D., Gan, Y., Chen, Z., Chen, Y., & Han, X. (2024) · Environmental Pollution · doi:10.1016/j.envpol.2024.125322 · Cited by 3 · see citing works
Shui, X., Zheng, X., Wu, J., Zhang, M., Kim, G., Chen, R., Peng, L., Wang, Z., Zheng, Y., Zhang, L., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00911-3 · Cited by 3 · see citing works
“The time each mouse spent for each object was calculated by Smart software and the recognition index was calculated [46].”
Chronic stress induces Alzheimer’s disease-like pathologies through DNA damage-Chk1-CIP2A signaling
Wang, Z., Zhang, L., Yang, J., Zeng, Y., Su, C., Yao, M., Zhang, H., Hu, W., Liu, Y., Lai, Y., et al. (2024) · Aging · doi:10.18632/aging.205862 · Cited by 3 · see citing works
Self-citationEstrella, L. D., Xu, X., White, C., Manganaro, J. E., Sheldon, L., Farmer, T., & Stauch, K. L. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.107084 · Cited by 2 · see citing works
“…LTP and LTD were predicted to be inactivated in the synaptosomes of hTau mice, similar reports using functional approaches have shown that LTP and overall synaptic plasticity are diminished in both hTau mice and other AD-related models (Fa et al., 2016; Polydoro et al., 2009; Shentu et al., 2018).”
Lentinan attenuates tau phosphorylation and memory deficits in hTau-overexpressing mice
Li, Y., & Chen, J. (2026) · Brain Research · doi:10.1016/j.brainres.2026.150340 · Cited by 2 · see citing works
Ribaudo, G., Pagano, M. A., Anyanwu, M., Giannangeli, M., Vezzoli, M., Visentin, A., Frezzato, F., Trentin, L., Brunati, A. M., & Gianoncelli, A. (2025) · Macromol—A Journal of Macromolecular Research · doi:10.3390/macromol5030043 · Cited by 1 · see citing works
Sundaresh, S. N., Vogel, E. W., Hue, C. D., Zhang, H., Staniszewski, A., Berman, H. L., Gill, Z., Asam, K. R., Liang, S., Shen, L., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70947 · Cited by 1 · see citing works
“Grant/AwardNumbers:W81XWH-12-1-0579, W81XWH-15-1-0550,HT9425-23-1-0384 Alzheimer’s disease, cognitive dysfunction, neurodegeneration, protein phosphatase 2A, tau, traumatic brain injury”
Cinco siglos circunnavegando el planeta
González, F. J. G. (2012) · Boletín de la Institución Libre de Enseñanza · Cited by 1 · see citing works
Cade, S., Prestidge, C. A., Zhou, X., & Bobrovskaya, L. (2024) · Ibrain · doi:10.1002/ibra.12187 · Cited by 1 · see citing works
Speranza, L., Filiz, K. D., Goebel, S., Perrone-Capano, C., Pulcrano, S., Volpicelli, F., & Francesconi, A. (2022) · bioRxiv · doi:10.1101/2022.09.20.508741
Fan, Y., Guo, C., Zhao, L.-X., Ge, R., Pang, Z.-Q., He, D., Ren, H., Zhang, Y., & Wang, Z. (2022) · doi:10.22541/au.167112371.14701167/v1 · Cited by 1 · see citing works
Ye, J., Yue, R.-Z., Li, C., Wu, L., Guo, X., Zhao, Y., Wan, H., Wang, J.-Z., Gu, B., & Xiao, S. (2025) · Research Square · doi:10.21203/rs.3.rs-7655539/v1
Self-citationLiu, Q., Sun, Y.-M., Huang, H., Chen, C., Wan, J., Ma, L.-H., Sun, Y.-Y., Miao, H.-H., & Wu, Y.-Q. (2021) · Figshare · doi:10.6084/m9.figshare.13719237
Li, L.-J., Sun, X.-Y., Huang, Y., Lu, S., Xu, Y.-M., Yang, J., Xie, X.-X., Zhu, J., Niu, X.-Y., Wang, D., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26488356
Self-citationYang, L., Song, G., Parker, E., & Yang, L. (2026) · Molecular Neurobiology · doi:10.1007/s12035-026-05832-w
Chen, W., Kainoh, K., Saito, K., Matsuda, T., Yamazaki, D., Kobari, Y., Nakata, A., Aono-Soma, N., Miyamoto, T., Murayama, Y., et al. (2026) · The FASEB Journal · doi:10.1096/fj.202602322r
- Authors
- Shentu, Y.-P., Huo, Y., Feng, X.-L., Gilbert, J., Zhang, Q., Liuyang, Z.-Y., Wang, X.-L., Wang, G., Zhou, H., Wang, X.-C., Wang, J.-Z., Lu, Y.-M., Westermarck, J., Man, H.-Y., & Liu, R.
- Affiliations
- Huazhong University of Science and Technology (CN)
- Boston University (US)
- Åbo Akademi University (FI)
- Corresponding author
- Man, Heng-Ye
- Liu, Rong
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 24
- Issue
- 3
- Pages
- 713-723
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6095478
- OpenAlex
- W2883780404
- Semantic Scholar
- c22ccb339c590eaff916d571d37c970a0238b6ec
- Cited by
- 90
- References
- 45
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 11 · 2023: 10 · 2022: 19 · 2021: 10 · 2020: 13 · 2019: 6 · 2018: 3 · 2012: 1
- FWCI
- 5.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- UTUPub (University of Turku) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81471304, 31771189)
- Natural Science Foundation of Hubei Province, China (2017CFA065)
- Integrated Innovative Team for Major Human Diseases Program of Tongji Medical College, HUST
- NIH (R01MH079407)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- CIP2A, protein phosphatase 2A, Alzheimer's disease, tau hyperphosphorylation, amyloid precursor protein, amyloid-beta production, synaptopathy, synaptic degeneration, long-term potentiation, memory impairment, AAV gene delivery, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Autoantigens, Brain, Hippocampus, Humans, Membrane Proteins, Memory Disorders, Mice, Inbred C57BL, Nerve Degeneration, Neurons, Phosphorylation, Synapses, Amyloid beta-Peptides, tau Proteins, Rats, Sprague-Dawley, Long-Term Potentiation, Intracellular Signaling Peptides and Proteins, Protein Phosphatase 2, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
