ArticleThe American journal of pathology2003
Activation of the ERK and JNK signaling pathways caused by neuron-specific inhibition of PP2A in transgenic mice.
Article in The American journal of pathology, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed, 154 citations in OpenAlex.
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- Synergistic neuroprotective effects of Vitexin and Thymol against Okadaic acid-induced neurotoxicity: Computational and In vitro evaluation.Molecular biology reports · 2025Article
- Targeting PP2A in cancer: an underrated option.Journal of experimental & clinical cancer research : CR · 2025Review
- Pathological Calcium Signaling in Traumatic Brain Injury and Alzheimer's Disease: From Acute Neuronal Injury to Chronic Neurodegeneration.International journal of molecular sciences · 2025Review
- IGF1R/ARRB1 Mediated Regulation of ERK and cAMP Pathways in Response to Aβ Unfolds Novel Therapeutic Avenue in Alzheimer's Disease.Molecular neurobiology · 2025Article
- Cellular and molecular mechanisms of pathological tau phosphorylation in traumatic brain injury: implications for chronic traumatic encephalopathy.Molecular neurodegeneration · 2025Review
- LncRNA ENST00000440246.1 Promotes Alzheimer's Disease Progression by Targeting PP2A.Biochemical genetics · 2024Article
- miRNAs and Stem Cells as Promising Diagnostic and Therapeutic Targets for Alzheimer's Disease.Journal of Alzheimer's disease : JAD · 2023Review
- Interdisciplinary Approaches to Deal with Alzheimer's Disease-From Bench to Bedside: What Feasible Options Do Already Exist Today?Biomedicines · 2022Review
- Article
- BCI, an inhibitor of the DUSP1 and DUSP6 dual specificity phosphatases, enhances P2X7 receptor expression in neuroblastoma cells.Frontiers in cell and developmental biology · 2022Article
- A ß-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration.Frontiers in pharmacology · 2021Article
- Leucine Carboxyl Methyltransferase 1 Overexpression Protects Against Cognitive and Electrophysiological Impairments in Tg2576 APP Transgenic Mice.Journal of Alzheimer's disease : JAD · 2021Article
- Stem cell therapy for Alzheimer's disease.World journal of stem cells · 2020Review
- Gamma radiation improves AD pathogenesis in APP/PS1 mouse model by potentiating insulin sensitivity.Heliyon · 2020Article
- Effects of Bisphenol A on Oxidative Stress in the Rat Brain.Antioxidants (Basel, Switzerland) · 2020Article
- PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: A Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder.International journal of molecular sciences · 2020Review
- Chronic Sodium Selenate Treatment Restores Deficits in Cognition and Synaptic Plasticity in a Murine Model of Tauopathy.Frontiers in molecular neuroscience · 2020Article
- To be or not to be: PP2A as a dual player in CNS functions, its role in neurodegeneration, and its interaction with brain insulin signaling.Cellular and molecular life sciences : CMLS · 2019Review
- The Anti-Tumor Agent Sodium Selenate Decreases Methylated PP2A, Increases GSK3βY216 Phosphorylation, Including Tau Disease Epitopes and Reduces Neuronal Excitability in SHSY-5Y Neurons.International journal of molecular sciences · 2019Article
12 more citing papers are in PubMed but not listed here.
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4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A reduced activity of protein phosphatase 2A (PP2A) has been shown in brains of patients with Alzheimer's disease (AD), a neurodegenerative disorder characterized histopathologically by amyloid plaques and neurofibrillary tangles. Tau, as the principal component of neurofibrillary tangles, can be hyperphosphorylated by a reduced activity of PP2A in vitro and by pharmacological approaches, suggesting a crucial role of PP2A in tangle formation. To dissect the role of PP2A in vivo, we previously generated transgenic mice with chronically reduced PP2A activity by expressing a dominant-negative mutant form of the PP2A catalytic subunit Calpha, L199P, under the control of a neuron-specific promoter. In these mice, endogenous tau is phosphorylated at the epitopes Ser202/Thr205 and Ser422. In vitro, these tau phospho-epitopes can be phosphorylated by the kinases ERK and JNK, and the kinases themselves are negatively regulated by PP2A. In this study, we show that chronic inhibition of PP2A activity in L199P transgenic mice causes the activation of ERK and JNK as demonstrated by the phosphorylation and nuclear accumulation of the ERK and JNK substrates, Elk-1 and c-Jun. TUNEL staining revealed that activated JNK signaling was not associated with cell death. Our findings imply that PP2A is a negative regulator of the ERK and JNK signaling pathways in vivo, suggesting that in AD, tau hyperphosphorylation may be caused in part by PP2A dysfunction.
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