Okadaic acid induced neurotoxicity: An emerging tool to study Alzheimer's disease pathology

Kamat, Pradip K.; Rai, Shivika; Nath, Chandishwar

doi:10.1016/j.neuro.2013.05.002

Cited by 117 publications

(62 citation statements)

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“…Activation of protein kinase and/or inhibition of protein phosphatases are the likely cause(s) of tau hyper-phosphorylation . OA, a phosphatase 2A inhibitor, has been used widely to induce hyper-phosphorylation of tau in order to stimulate neural death in culture and enhance Aβ deposition, synaptic loss, as well as memory impairment in AD animal models (Barrio et al, 2011;Li et al, 2011;Kamat et al, 2013). CTX0E03 cells were exquisitely susceptible to OA cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

P3‐136: A Genetically Immortalized Human Stem Cell Line: A Promising New Tool for Alzheimer’s Disease Therapy

Puangmalai

Thangnipon

Somani

et al. 2016

Alzheimer's & Dementia

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Amyloid-β peptides and hyper-phosphorylated tau are the main pathological hallmarks of Alzheimer's disease (AD). Given the recent failure of several large-scale clinical trials and the lack of disease-modifying pharmacological treatments, there is an urgent need to develop alternative therapies. A clinical grade human CTX0E03 neural stem cell line has recently passed phase I trials in people with stroke. However, this cell line has not been investigated in other neurodegenerative disorders. This study investigates the survival of CTX0E03 cells under conditions based on the underlying AD pathology. Cell viability assays showed a concentration dependence of this cell line to the toxic effects of Aβ 1-42 , but not Aβ 1-40 , and okadaic acid, a phosphatase 2A inhibitor. Notably, CTX0E03 cell line displayed toxicity at concentrations significantly higher than both rat neural stem cells and those previously reported for primary cultures. These results suggest CTX0E03 cells could be developed for clinical trials in AD patients.

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Section: Discussionmentioning

confidence: 99%

P3‐136: A Genetically Immortalized Human Stem Cell Line: A Promising New Tool for Alzheimer’s Disease Therapy

Puangmalai

Thangnipon

Somani

et al. 2016

Alzheimer's & Dementia

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“…A ação tóxica dos okadaiatos, verificada em ensaios biológicos e citológicos, é classificada em: genotóxica (Silva et al 2001), carcinogênica (Feng et al 2006), neurotóxica (Kamat et al 2013) e citotóxica (Huynh-Delerme et al 2003).…”

Section: Toxinas Diarreicasunclassified

The Role of Diarroethic Phycotoxins in Aquatic Biota Andaquaculture

Ferreira

Pereira

2016

Oecol. Austr.

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RESUMOO presente artigo contextualiza o papel das ficotoxinas diarreicas em três cenários: seu papel ecológico em relação à biota marinha, seus efeitos na aquicultura e, incluindo o homem na teia trófica marinha, seus efeitos deletérios na saúde pública. Primeiramente, ficotoxinas são definidas como produtos naturais marinhos, substâncias biologicamente ativas (metabólitos secundários), sendo as diarreicas sintetizadas por dinoflagelados dos gêneros Dinophysis e Prorocentrum. Esses organismos integram a comunidade planctônica marinha costeira, sendo algumas espécies de Prorocentrum bentônicas; portanto as toxinas apresentam implicações nas teias tróficas pelágicas e bentônicas costeiras. São ditas microalgas potencialmente tóxicas, pois a produção das ficotoxinas não é constante e varia intraespecificamente dependendo do contexto ecológico em que a microalga se encontre. Moluscos bivalvos (mexilhões, ostras e vieiras) são o segundo grupo mais cultivado na aquicultura marinha. São organismos bentônicos sésseis e alimentam-se principalmente de microalgas. Quando as microalgas potencialmente tóxicas estiverem expressando sua capacidade toxígena, os moluscos as bioacumularão, transferindo as ficotoxinas para os consumidores humanos. Dessa forma, surgem as Síndromes de Envenenamento por Moluscos, maior problema de saúde pública em nível mundial, associadas ao consumo de moluscos bivalvos contaminados por ficotoxinas. Essa revisão trata especificamente do Envenenamento Diarreico por Moluscos (EDM), intoxicação causada principalmente pela ficotoxina ácido okadáico, amplamente distribuída em águas temperadas às tropicais. Atualmente, a aquicultura corresponde a 47% do pescado produzido, com tendência a aumentar sua participação em virtude da estagnação na captura de pescado. Dessa forma, para garantir que o pescado produzido seja um alimento inócuo aos consumidores humanos, foi necessário desenvolver políticas públicas voltadas à sanidade do pescado. No cenário nacional, recentemente foi criado o Programa Nacional de Controle Higiênico Sanitário de Moluscos Bivalvos, ainda não implementado, em moldes de programas internacionais em vigor há décadas. A plena execução do programa é fundamental ao fomento seguro da aquicultura nacional. Palavras-chave: Dinophysis; envenenamento diarreico por moluscos; ficotoxinas; malacocultura; Prorocentrum. ABSTRACT -THE ROLE OF DIARROETHIC PHYCOTOXINS IN AQUATIC BIOTA ANDAQUA-CULTUREThis article analyzes the role of diarroethic phycotoxins in three scenarios: their ecological role in relation to marine biota, their effects on aquaculture -including the man in the marine trophic web -and its deleterious effects on public health. First, phycotoxins are defined as marine natural products. Biologically active (secondary metabolites) being the diarroethic ones-synthesized by dinoflagellates from the genus Dinophysis and Prorocentrum. These dinoflagellates comprise the coastal marine plankton community, but some species of toxic Prorocentrum are benthic. So the toxins have implications for ben...

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“…In chapter 3 we sought to establish a mouse model whereby mechanisms involved in the presumably prion-like spreading of tau could be investigated in the absence of a human transgene. Previously, because tau is hyperphosphorylated and PP2A is a major tau phosphatase, the PP2A inhibitor OA has been used, predominantly by chronic exposure in rats, to recapitulate multiple aspects of AD pathology [119,120]. By reducing the injection concentration and volume we achieved restricted exposure to OA unilaterally in the lateral amygdala (a site with pronounced tau pathology in AD), while leaving other brain structures such as the hippocampus and cortex and the entire contralateral hemisphere as OA-unexposed read-out regions.…”

Section: Discussionmentioning

confidence: 99%

“…The induced inhibition causes tau hyperphosphorylation, which is further exacerbated by OA dependent increase in kinase activity [119]. The compound has been extensively applied to rat models of AD, and appears to reflect many of the dysfunctions across different modalities thought to underlie human AD including mature NFTS and neuronal loss (reviewed in [119,120]). A feat that may not be reliant solely on tau hyperphosphorylation, but also due to OA's potent induction of oxidative stress [119].…”

Section: Chemical Modelsmentioning

confidence: 99%

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Investigating in vivo the principles governing the spread of tau phosphorylation and amyloid-beta excitotoxicity

Baker¹

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Alzheimers disease (AD) is a devastating neurodegenerative disease which presents clinically with progressive loss of memory, executive function and cognitive abilities.Traditionally AD is diagnosed post-mortem by presence of two hallmark lesions, extracellular plaques comprised of amyloid-beta (Aβ) and intracellular neurofibrillary tangles (NFTs) containing hyperphosphorylated microtubule-associated protein tau.The current available therapies for the treatment of AD only provide mild symptomatic relief and cannot halt the ongoing disease progression. Therefore, the research presented focuses on the mechanisms underlying disease propagation specifically that of hyperphosphorylated tau pathology, and understanding potential disease modifying therapeutics targeting known mechanisms, specifically TatNR2b9c peptide induced neuroprotection against Aβ induced excitotoxicity.Current approaches to investigate tau propagation have utilised tau transgenic recipient mice, mutant tagged tau constructs and whole brain lysates to establish tau seeding and spreading in vitro. To circumvent caveats of this technique and progress our understanding of tau seeding events we proposed a two-pronged approach.Firstly, we created an endogenous model of tau hyperphosphorylation by inhibiting tau dephosphorylation with the unilateral injection of the inhibitor okadaic acid. By keeping the concentration and volume low we were able to show by ELISA that the spread of the inhibitor could be restricted, and this single exposure was sufficient to induce tau hyperphosphorylation, increases in insolubilty and thioflavin-S NFT-Like immunoreactivity at both the injection site and anatomically distinct non-exposed brain regions. Secondly, we injected exosome and large extracellular vesicle fractions derived from tau transgenic mice into human tau expressing mice and compared there seeding ability to brain lysate. Under our experiment parameters we did not observe any NFT positivity and could not recreate previous seeding using brain lysates. Interestingly, both brain lysates and exosomes increased AT8 phosphorylation and oligomeric tau deposition in the hippocampus, whereas large extracellular vesicles did not.To address whether the Tat-NR2b9c peptide can provide long-term protection against Aβ induced excitotoxicity we treated mutant amyloid precursor protein 3 transgenic mice at both young and old age and investigated amyloid levels and NMDA receptor subunit expression in synaptic and extrasynaptic zones.Unfortunately, lack of a robust behavioural deficit in our aged APP23 cohort prevented us from performing a therapeutic intervention study. However, biochemical analysis of aged Tat-NR2b9c revealed a similar effect on synaptic redistribution of NMDA receptor subunits as that observed in young treated mice, indicating that the peptide may be a viable therapeutic prospect for late stage intervention in AD.This work demonstrates that mechanisms underlying tau spreading may also be studied by using endogenous mouse tau models. An avenue whic...

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Okadaic acid induced neurotoxicity: An emerging tool to study Alzheimer's disease pathology

Cited by 117 publications

References 119 publications

P3‐136: A Genetically Immortalized Human Stem Cell Line: A Promising New Tool for Alzheimer’s Disease Therapy

P3‐136: A Genetically Immortalized Human Stem Cell Line: A Promising New Tool for Alzheimer’s Disease Therapy

The Role of Diarroethic Phycotoxins in Aquatic Biota Andaquaculture

Investigating in vivo the principles governing the spread of tau phosphorylation and amyloid-beta excitotoxicity

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