RETRACTED: 5‐Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of alzheimer disease

Chu, Jin; Giannopoulos, Phillip F.; Ceballos‐Diaz, Carolina; Golde, Todd E.; Praticò, Domenico

doi:10.1002/ana.23642

Cited by 74 publications

(106 citation statements)

References 30 publications

(88 reference statements)

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“…This concentration and incubation time were chosen based on previous studies conducted by our group. Specifically, we found that this concentration and incubation time produced the most efficient effect of suppressing cdk5 activity (Chu et al ., 2012b). As seen in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The cells were cultured to 70% confluence in six‐well plates and then transfected with 1 μg empty vector or human 5LO pcDNA3.1 (Dr. Colin Funk, Queen's University, Kingston, Canada) using Lipofectamine reagent (Invitrogen) according to the manufacturer's instructions and as previously described (Chu et al ., 2012b). After 48‐h treatment, supernatants were collected and cell harvested in lytic buffer for biochemistry analyses.…”

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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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

2017

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“…We utilized We corroborated these findings of Aβ pathology in the 3xTg mouse and found that additionally, 5LO also acts on tau metabolism. Genetic unavailability of 5LO or its overexpression correlates directly with increased and diminished, respectively, tau phosphorylation, insoluble tau aggregation and NFT development [35,36]. We have shown that this aspect of 5LO is mediated by the cyclin-dependent kinase 5 (cdk5) [37].…”

Section: -Lipoxygenase: a Modulator The Alzheimer's Disease Phenotypementioning

confidence: 98%

Neuroinflammation and Alzheimer’s disease: lessons learned from 5-lipoxygenase

Joshi

Praticò

2014

Translational Neuroscience

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Aside from the well-known amyloid beta and tau pathologies found in Alzheimer's disease (AD), neuroinflammation is a well-established aspect described in humans and animal models of the disease. Inflammatory perturbations are evident not only in neurons, but also in non-neuronal cells and cytokines in the AD brain. Although the amyloid hypothesis implicates amyloid beta (Aβ) as the prime initiator of the AD, brain inflammation in AD has a complex relationship between Aβ and tau. Using our work with the 5-lipoxygenase protein as an example, we suggest that at least in the case of AD, there is an interdependent and not necessarily hierarchical pathological relationship between Aβ, tau and inflammation.

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“…In vivo overexpression of 5-LOX increases phosphorylation of specific Tau epitopes, and neuronal cells transfected with 5-LOX show a significant increase in tau phosphorylation even when their ability to generate Aβ is completely blocked, suggesting that the effect on tau is independent from Aβ (Chu et al, 2012). Interestingly, Tau-mice treated with zileuton (a potent 5-LOX inhibitor) displayed a significant improvement in memory and synaptic function together with a decreased tau phosphorylation level (Chu and Pratico, 2013;Giannopoulos et al, 2014).…”

Section: How Do N-3 Pufa Mechanisms Control Neuroinflammation?mentioning

confidence: 99%

N-3 PUFAs and neuroinflammatory processes in cognitive disorders

Leyrolle

Layé

Nadjar

2016

OCL

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-With the ageing population and increased cases of neurodegenerative diseases, there is a crucial need for the development of new nutritional approaches to prevent and delay the onset of cognitive decline. Neuroinflammatory processes contribute to neuronal damage that underpins neurodegenerative disorders. Growing evidence sheds light on the use of dietary n-3 long chain polyunsaturated fatty acids to improve cognitive performances and reduce the neuroinflammatory responses occurring with age and neurodegenerative pathologies. This review will summarise the most recent information related to the impact and mechanisms underlying the neuroinflammatory processes in cognitive disorders. We will also discuss the mechanisms underlying n-3 polyunsaturated fatty acids effect on neuroinflammation and memory decline.Keywords: Neuroinflammation / microglia / n-3 polyunsaturated fatty acids / cognitive disorders / Alzheimer disease Résumé -Acides gras polyinsaturés de la famille des oméga 3, processus neuroinflammatoires et troubles cognitifs. Le développement d'approches nutritionnelles pertinentes pour prévenir et retarder l'apparition du déclin cognitif est un enjeu important, compte tenu du vieillissement de la population et de l'augmentation de l'incidence des maladies neurodégénératives. Les processus neuro-inflammatoires contribuent aux mécanismes neuropathologiques impliqués dans les troubles neurodégénératifs et de la cognition. Des données récentes indiquent l'importance des acides gras polyinsaturés n-3 alimentaires dans le maintien des performances mnésiques et la régulation de la neuroinflammation liée à l'âge ou à la maladie d'Alzheimer. Dans cette revue, seront présentées des données récentes sur les liens existants entre le statut nutritionnel en acides gras polyinsaturés n-3, les processus neuro-inflammatoires et les troubles cognitifs associés, ainsi que les mécanismes qui pourraient être impliqués dans les effets protecteurs de ces acides gras.

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RETRACTED: 5‐Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of alzheimer disease

Cited by 74 publications

References 30 publications

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

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

Neuroinflammation and Alzheimer’s disease: lessons learned from 5-lipoxygenase

N-3 PUFAs and neuroinflammatory processes in cognitive disorders

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