Okadaic acid-induced Tau phosphorylation in rat brain: Role of NMDA receptor

Kamat, Pradeep K.; Rai, Shivika; Swarnkar, Supriya; Shukla, Rakesh; Ali, Shakir; Najmi, Abul Kalam; Nath, Chandishwar

doi:10.1016/j.neuroscience.2013.01.075

Cited by 75 publications

(45 citation statements)

References 45 publications

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“…Therefore, the abnormal phosphorylation of tau observed herein in hippocampus, might be as a result of decrease in p-GSK3, but also by diminished dephosphorylating activity of PP2A. In agreement with this, the inhibition of PP2A with okadaic acid (OKA), i.e., a potent and selective inhibitor of PP2A and PP1, produces memory impairment in the Morris water maze and oxidative stress, treatment with memantine (10 mg/kg, po) or donepezil (5 mg/kg, po) for 13 days post-OKA, improves memory and reduces oxidative stress [75].…”

Section: Discussionmentioning

confidence: 65%

Role of GSK3<i>β</i> and PP2A on Regulation of Tau Phosphorylation in Hippocampus and Memory Impairment in ICV-STZ Animal Model of Alzheimer’s Disease

Ponce-López¹,

Hong²,

Abascal-Díaz³

et al. 2017

AAD

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Intracerebroventricular administration (ICV) of streptozotocin (STZ) in rats has been associated to desensitization of the insulin receptor (IR) and biochemical changes similar to those occurring in Alzheimer's disease (AD) or older brains, so it has been proposed as a suitable model for studying some of the pathological features of AD sporadic type (SAD). In this study, we investigated the role of glycogen synthase kinase 3β (GSK3β) and protein phosphatase 2A (PP2A) in the regulation of the phosphorylation of tau (p-tau). Results showed that ICV-STZ treated rats had deficits in short-(1.5-h) and long-term (24-and 48-h) memory after one month of ICV-STZ treatment and six months relative to control rats. The memory deficit was associated to increasing [F(3, 12) = 31.48, p < 0.0001] p-tau in the hippocampus but not in prefrontal cortex (PFC). Likewise, STZ reduced phosphorylation of GSK3β (p-GSK3β) and PP2A in hippocampus and PFC, indicating that GSK3β and PP2A contributed to regulation of p-tau. These data supporting the model with ICV-STZ in rat are adequate to study the progressive memory impairment associated to hyperphosphorylation of tau and the cascade of insulin receptor signaling; confirm that phosphatidyl-inositol-3 kinase-protein kinase B (PI3K-PKB/Akt-GSK3β) and PP2A are involved in the modulation of proteins responsible for the regulation of neurodegeneration in AD.

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Section: Discussionmentioning

confidence: 65%

Role of GSK3<i>β</i> and PP2A on Regulation of Tau Phosphorylation in Hippocampus and Memory Impairment in ICV-STZ Animal Model of Alzheimer’s Disease

Ponce-López¹,

Hong²,

Abascal-Díaz³

et al. 2017

AAD

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“…These results were similar to those obtained with IMM-H004. Kamat et al indicated that donepezil could improve OKA-induced memory damage by increasing PP2A expression [25] , which decreased hyperphosphorylation of tau, or by increasing cholinergic function [26] . Noh et al [27] showed that donepezil improved Aβ1-42-induced neurotoxicity through activation of PP2A, which could decrease hyperphosphorylation of tau.…”

Section: Discussionmentioning

confidence: 99%

A new coumarin derivative, IMM-H004, attenuates okadaic acid-induced spatial memory impairment in rats

et al. 2016

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Aim: A novel coumarin derivative 7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-coumarin (IMM-H004) has shown antiapoptotic, anti-inflammatory and neuroprotective activities. In this study we investigated the effects of IMM-H004 on spatial memory in rats treated with okadaic acid (OKA), which was used to imitate Alzheimer's disease (AD)-like symptoms. Methods: SD rats were administered IMM-H004 (8 mg·kg -1 ·d -1 , ig) or donepezil (positive control, 1 mg·kg -1 ·d -1 , ig) for 25 d. On d 8 and 9, OKA (200 ng) was microinjected into the right ventricle. Morris water maze test was used to evaluate the spatial memory impairments. Tau and β-amyloid (Aβ) pathology in the hippocampus was detected using Western blot and immunohistochemistry. TUNEL staining was used to detect cell apoptosis. Results: OKA-treated rats showed significant impairments of spatial memory in Morris water maze test, which were largely reversed by administration of IMM-H004 or donepezil. Furthermore, OKA-treated rats exhibited significantly increased phosphorylation of tau, deposits of Aβ protein and cell apoptosis in the hippocampus, which were also reversed by administration of IMM-H004 or donepezil. Conclusion: Administration of IMM-H004 or donepezil protects rats against OKA-induced spatial memory impairments via attenuating tau or Aβ pathology. Thus, IMM-H004 may be developed as a therapeutic agent for the treatment of AD.

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“…Neurodegenerative disorders are characterized by progressive cell loss in specific neuronal populations and mechanisms that have been put forward to account for AD with aging including inflammation and oxidative stress [7, 8]. Recently, Rai et al [9] also proved that NMDAR activation, excessive Ca 2+ fluxes, and free radical generation are associated with synaptic dysfunction and tau phosphorylation [10]. Excessive amounts of glutamate are associated with intense transient influx of Ca 2+ , leading to mitochondrial functional impairments characterized by activation of the permeability transition pores in the inner mitochondrial membrane, cytochrome c release and depletion of ATP, and simultaneous formation of ROS [11].…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer’s Disease: Understanding the Therapeutics Strategies

et al. 2014

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Synapses are formed by interneuronal connections that permit a neuronal cell to pass an electrical or chemical signal to another cell. This passage usually gets damaged or lost in most of the neurodegenerative diseases. It is widely believed that the synaptic dysfunction and synapse loss contribute to the cognitive deficits in patients with Alzheimer’s disease (AD). Although pathological hallmarks of AD are senile plaques, neurofibrillary tangles, and neuronal degeneration which are associated with increased oxidative stress, synaptic loss is an early event in the pathogenesis of AD. The involvement of major kinases such as mitogen-activated protein kinase (MAPK), extracellular receptor kinase (ERK), calmodulin-dependent protein kinase (CaMKII), glycogen synthase-3β (GSK-3β), cAMP response element-binding protein (CREB), and calcineurin is dynamically associated with oxidative stress-mediated abnormal hyperphosphorylation of tau and suggests that alteration of these kinases could exclusively be involved in the pathogenesis of AD. N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation and beta amyloid (Aβ) toxicity alter the synapse function, which is also associated with protein phosphatase (PP) inhibition and tau hyperphosphorylation (two main events of AD). However, the involvement of oxidative stress in synapse dysfunction is poorly understood. Oxidative stress and free radical generation in the brain along with excitotoxicity leads to neuronal cell death. It is inferred from several studies that excitotoxicity, free radical generation, and altered synaptic function encouraged by oxidative stress are associated with AD pathology. NMDARs maintain neuronal excitability, Ca2+ influx, and memory formation through mechanisms of synaptic plasticity. Recently, we have reported the mechanism of the synapse redox stress associated with NMDARs altered expression. We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.

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Okadaic acid-induced Tau phosphorylation in rat brain: Role of NMDA receptor

Cited by 75 publications

References 45 publications

Role of GSK3<i>β</i> and PP2A on Regulation of Tau Phosphorylation in Hippocampus and Memory Impairment in ICV-STZ Animal Model of Alzheimer’s Disease

Role of GSK3<i>β</i> and PP2A on Regulation of Tau Phosphorylation in Hippocampus and Memory Impairment in ICV-STZ Animal Model of Alzheimer’s Disease

A new coumarin derivative, IMM-H004, attenuates okadaic acid-induced spatial memory impairment in rats

Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer’s Disease: Understanding the Therapeutics Strategies

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Okadaic acid-induced Tau phosphorylation in rat brain: Role of NMDA receptor

Cited by 75 publications

References 45 publications

Role of GSK3&lt;i&gt;β&lt;/i&gt; and PP2A on Regulation of Tau Phosphorylation in Hippocampus and Memory Impairment in ICV-STZ Animal Model of Alzheimer’s Disease

Role of GSK3&lt;i&gt;β&lt;/i&gt; and PP2A on Regulation of Tau Phosphorylation in Hippocampus and Memory Impairment in ICV-STZ Animal Model of Alzheimer’s Disease

A new coumarin derivative, IMM-H004, attenuates okadaic acid-induced spatial memory impairment in rats

Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer’s Disease: Understanding the Therapeutics Strategies

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Role of GSK3<i>β</i> and PP2A on Regulation of Tau Phosphorylation in Hippocampus and Memory Impairment in ICV-STZ Animal Model of Alzheimer’s Disease

Role of GSK3<i>β</i> and PP2A on Regulation of Tau Phosphorylation in Hippocampus and Memory Impairment in ICV-STZ Animal Model of Alzheimer’s Disease