Zileuton restores memory impairments and reverses amyloid and tau pathology in aged Alzheimer's disease mice

Meco, Antonio Di; Lauretti, Elisabetta; Vagnozzi, Alana N.; Praticò, Domenico

doi:10.1016/j.neurobiolaging.2014.05.016

Cited by 60 publications

(63 citation statements)

References 17 publications

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“…Samples were centrifuged at 15.7 g for 20 min at 4 °C, and supernatants were used for immunoblot analysis, as previously described (Di Meco et al ., 2014). Total protein concentration was determined using BCA Protein Assay Kit (Pierce, Rockford, IL, USA).…”

Section: Methodsmentioning

confidence: 99%

Glucose deprivation increases tau phosphorylation via P38 mitogen‐activated protein kinase

Lauretti

Praticò

2015

Aging Cell

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SummaryAlterations of glucose metabolism have been observed in Alzheimer's disease (AD) brain. Previous studies showed that glucose deprivation increases amyloidogenesis via a BACE‐1‐dependent mechanism. However, no data are available on the effect that this condition may have on tau phosphorylation. In this study, we exposed neuronal cells to a glucose‐free medium and investigated the effect on tau phosphorylation. Compared with controls, cells incubated in the absence of glucose had a significant increase in tau phosphorylation at epitopes Ser202/Thr205 and Ser404, which was associated with a selective activation of the P38 mitogen‐activated protein kinase. Pharmacological inhibition of this kinase prevented the increase in tau phosphorylation, while fluorescence studies revealed its co‐localization with phosphorylated tau. The activation of P38 was secondary to the action of the apoptosis signal‐regulating kinase 1, as its down‐regulation prevented it. Finally, glucose deprivation induced cell apoptosis, which was associated with a significant increase in both caspase 3 and caspase 12 active forms. Taken together, our studies reveal a new mechanism whereby glucose deprivation can modulate AD pathogenesis by influencing tau phosphorylation and suggest that this pathway may be a new therapeutic target for AD.

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Section: Methodsmentioning

confidence: 99%

Glucose deprivation increases tau phosphorylation via P38 mitogen‐activated protein kinase

Lauretti

Praticò

2015

Aging Cell

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“…Testing was always performed in the same room and at the same time to ensure environmental consistency as previously described (Di Meco, Lauretti, Vagnozzi & Praticò, 2014; Giannopoulos et al., 2013). Briefly, each mouse was placed in the center of the Y‐maze and allowed to explore freely during a 5‐min session as a measure of spontaneous alternating behavior.…”

Section: Methodsmentioning

confidence: 99%

Antileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice

2018

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SummaryThe 5‐lipoxygenase (5LO) is a source of inflammatory leukotrienes and is upregulated in Alzheimer's disease and related tauopathies. However, whether it directly modulates tau phosphorylation and the development of its typical neuropathology in the absence of Aβ or is a secondary event during the course of the disease pathogenesis remains to be fully elucidated. The goal of this study was to evaluate the effect that pharmacologic blockade of this inflammatory pathway has on the phenotype of a transgenic mouse model of tauopathy, the P301S mice. Starting at 3 months of age, P301S mice were randomized to receive zileuton, a specific 5LO blocker, for 7 months; then, its effect on their behavioral deficits and neuropathology was assessed. Inhibition of leukotrienes formation was associated with a reduction in tau phosphorylation and an amelioration of memory and learning as well as synaptic integrity, which were secondary to a downregulation of the cdk5 kinase pathway. Our results demonstrate that the 5LO enzyme is a key player in modulating tau phosphorylation and pathology and that blockade of its enzymatic activity represents a desirable disease‐modifying therapeutic approach for tauopathy.

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“…Testing was always performed in the same room and at the same time to ensure environmental consistency as previously described (Di Meco et al ., 2014; Li et al ., 2014). Briefly, each mouse was placed in the center of the Y‐maze and allowed to explore freely during a 5‐min session as a measure of spontaneous alternating behavior.…”

Section: Methodsmentioning

confidence: 99%

“…Fear conditioning experiments were performed following methods previously described (Di Meco et al ., 2014, 2017) . Tests were conducted in a conditioning chamber equipped with black methacrylate walls, transparent front door, a speaker, and grid floor (Start Fear System; Harvard Apparatus)…”

Section: Methodsmentioning

confidence: 99%

“…To perform the Morris water maze (MWM), we used a white circular plastic tank (122 cm in diameter, walls 76 cm high), filled with water maintained at 22°±2°C, and made opaque by the addition of a nontoxic white paint, as previously described (Di Meco et al ., 2014; Li et al ., 2014). Mice were trained for four consecutive days to find a Plexiglas platform submerged in water from four different starting points.…”

Section: Methodsmentioning

confidence: 99%

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Brain 5‐lipoxygenase over‐expression worsens memory, synaptic integrity, and tau pathology in the P301S mice

2017

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SummaryProgressive accumulation of highly phosphorylated tau protein isoforms is the main feature of a group of neurodegenerative diseases collectively called tauopathies. Data from human and animal models of these diseases have shown that neuroinflammation often accompanies their pathogenesis. The 5‐lipoxygenase (5LO) is an enzyme widely expressed in the brain and a source of potent pro‐inflammatory mediators, while its pharmacological inhibition modulates the phenotype of a tau transgenic mouse model, the htau mice. By employing an adeno‐associated viral vector system to over‐express 5LO in the brain, we examined its contribution to the behavioral deficits and neuropathology in a different transgenic mouse model of tauopathy, the P301S mouse line. Compared with controls, 5LO‐targeted gene brain over‐expression in these mice resulted in a worsening of behavioral and motor deficits. Over‐expression of 5LO resulted in microglia and astrocyte activation and significant synaptic pathology, which was associated with a significant elevation of tau phosphorylation at specific epitopes, tau insoluble fraction, and activation of the cdk5 kinase. In vitro studies confirmed that 5LO directly modulates tau phosphorylation at the same epitopes via the cdk5 kinase pathway. These data demonstrate that 5LO plays a direct role in tau phosphorylation and is an active player in the development of the entire tau phenotype. They provide further support to the hypothesis that 5LO is a viable therapeutic target for the treatment and/or prevention of human tauopathy.

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Zileuton restores memory impairments and reverses amyloid and tau pathology in aged Alzheimer's disease mice

Cited by 60 publications

References 17 publications

Glucose deprivation increases tau phosphorylation via P38 mitogen‐activated protein kinase

Glucose deprivation increases tau phosphorylation via P38 mitogen‐activated protein kinase

Antileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice

Brain 5‐lipoxygenase over‐expression worsens memory, synaptic integrity, and tau pathology in the P301S mice

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