The 5-Lipoxygenase as a Common Pathway for Pathological Brain and Vascular Aging

Chu, Jin; Praticò, Domenico

doi:10.1155/2009/174657

Cited by 34 publications

(20 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, post-mortem studies have shown that 5LO levels are upregulated in AD and PSP patients, as well as in relevant mouse models of AD and other tauopathies in areas of the brain more vulnerable to neurodegeneration, such as cortex and hippocampus [5, 33–35]. Following this discover, in recent years, our group has demonstrated that 5LO is a key player in the development of the full pathological phenotype of these neurodegenerative disorders [7, 8].…”

Section: Tau and Tauopathiesmentioning

confidence: 99%

Novel Key Players in the Development of Tau Neuropathology: Focus on the 5-Lipoxygenase

Lauretti

Praticò

2018

JAD

Self Cite

View full text Add to dashboard Cite

Tauopathies belong to a large group of neurodegenerative diseases characterized by progressive accumulation of hyperphosphorylated tau. Tau is a microtubule binding protein which is necessary for their assembly and stability. However, tau affinity for microtubules mainly depends on its phosphorylation status, which is the result of a delicate balance between kinases and phosphatases activity. Any significant changes in this equilibrium can promote tau fibrillation, aggregation, neuronal dysfunction, and ultimately neuronal loss. Despite intensive research, the molecular mechanism(s) leading to tau hyperphosphorylation are still unknown and there is no cure for these diseases. Development of an effective strategy that successfully prevents tau excessive phosphorylation and/or tau aggregation may offer a real therapeutic opportunity for these less investigated neurodegenerative conditions. Beside tau, chronic brain inflammation is a common feature of all tauopathies and 5-lipoxygenase, an inflammatory enzyme, is upregulated in brain regions affected by tau pathology. Recently, in vitro studies and preclinical investigations with animal models of tauopathy have implicated 5-lipoxygenase in the regulation of tau phosphorylation through activation of the cyclin-dependent kinase 5 pathway, supporting the novel hypothesis that this protein is a promising therapeutic target for the treatment of tau opathies. In this article, we will discuss the contribution of the 5-lipoxygenase signaling pathway in the development of tau neuropathology, and the promising potential that drugs targeting this enzyme activation hold as a novel disease-modifying therapeutic approach for tauopathies.

show abstract

Section: Tau and Tauopathiesmentioning

confidence: 99%

Novel Key Players in the Development of Tau Neuropathology: Focus on the 5-Lipoxygenase

Lauretti

Praticò

2018

JAD

Self Cite

View full text Add to dashboard Cite

show abstract

“…5LO is found throughout the central nervous system, in both neuron and glia cells [17]. However, its expression levels are highest in the cortex and hippocampus areas, two regions that are particularly vulnerable to neurodegenerative insults [18, 19].…”

Section: -Lipoxygenase Pathway In Brain Aging and Alzheimer’s Diseasementioning

confidence: 99%

“…Since aging is one of the strongest risk factors for developing AD [17], initially it was proposed that this pathway could potentially be involved in brain aging and events germaine to the pathogenesis of AD [22]. Post-mortem studies have shown that compared with healthy controls, post-mortem AD brains had higher 5LO protein levels in cortex and hippocampus.…”

Section: -Lipoxygenase Pathway In Brain Aging and Alzheimer’s Diseasementioning

confidence: 99%

The 5-Lipoxygenase as modulator of Alzheimer’s γ-secretase and therapeutic target

Chu

Praticò

2016

Brain Research Bulletin

Self Cite

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is an age-related, neurodegenerative disorder characterized by cognitive impairment with memory loss, extracellular amyloid beta (Aβ) peptides aggregation, and intracellular hyper-phosphorylated tau neurofibrillary tangles (NFT) accumulation. Although the 5-lipoxygenase (5LO) protein enzyme is well known as an important modulators of oxidation and inflammation, recent work has highlighted the potential role that this pathway may play a direct role in AD pathogenesis. In this review article, we will discuss how the 5LO via the γ-secretase influences Aβ peptides formation, and other molecular pathologies including neuroinflammation, synaptic integrity, and cognitive functions, and provide an assessment of how targeting this protein could lead to novel therapeutics for AD and other related neurodegenerative disorders.

show abstract

“…Several lines of research have established the presence of the 5-lipoxygenase (5-LOX; EC 1.13.11.34) pathway in the central nervous system (CNS) (Chinnici et al, 2007; Chu and Praticò, 2009; Lindgren et al, 1984; Miyamoto et al, 1987; Ohtsuki et al, 1995). Information about the site and the cell types responsible for the synthesis of 5-LOX products, the inflammatory leukotrienes and the anti-inflammatory lipoxins (Radmark et al, 2007, Serhan et al, 2008) in the CNS points to brain region differences in leukotriene formation (Chinnici et al, 2007; Miyamoto et al, 1987) and indicates the possibility of transcellular biosynthesis of cysteinyl leukotrienes in neuronal and glial cells (Farias et al, 2007).…”

mentioning

confidence: 99%

5-Lipoxygenase in mouse cerebellar Purkinje cells

2010

View full text Add to dashboard Cite

It has been suggested that the enzymatic pathway of 5-lipoxygenase (5-LOX) influences brain functioning and pathobiology. The mRNAs for both the enzyme 5-LOX and its activating protein FLAP have been found in the cerebellum. In this work, we investigated the cellular expression of 5-LOX in the adult mouse cerebellar cortex. We used the in situ mRNA hybridization assay, immunocytochemistry, laser capture microdissection, and our previously developed method for assaying the DNA methylation status of a putative mouse 5-LOX promoter. Since both 5-LOX mRNA in situ hybridization signal and FLAP immunoreactivity co-localize with calbindin 28kD immunoreactivity (a Purkinje cell marker) but not with S-100β immunoreactivity (a Bergmann glia marker), the suggestion is that the 5-LOX pathway is expressed in cerebellar Purkinje cells. We found that methylation in the sites targeted by methylation-sensitive restriction endonucleases AciI and HinP1I but not BstUI and HpaII was greater in DNA samples obtained from a high-5-LOXexpressing cerebellar region (Purkinje cells) vs. a low-5-LOX-expressing region (the molecular cell layer), suggesting a possible epigenetic contribution to the cell-specific 5-LOX expression in the cerebellum. We propose that Purkinje cell-localized 5-LOX and FLAP expression may be involved in the cerebellar synthesis of leukotrienes and/or could influence the Dicer-mediated microRNA formation and processes of neuroplasticity. (Chinnici et al., 2007;Chu and Praticò, 2009;Lindgren et al., 1984;Miyamoto et al., 1987;Ohtsuki et al., 1995). Information about the site and the cell types responsible for the synthesis of 5-LOX products, the inflammatory leukotrienes and the anti-inflammatory lipoxins (Radmark et al., 2007, Serhan et al., 2008 in the CNS points to brain region differences in leukotriene formation (Chinnici et al., 2007;Miyamoto et al., 1987) and indicates the possibility of transcellular biosynthesis of cysteinyl leukotrienes in neuronal and glial cells (Farias et al., 2007). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 December 1. 5-LOX appears to be involved in mechanisms of cell proliferation and differentiation and in neuroplasticity, such as hedgehog-dependent neurite projection (Bijlsma et al., 2008). In the adult brain, in addition to their strong hippocampal expression, the mRNAs for both 5-LOX and its activating protein FLAP (5-lipoxygenase activating protein) were found in the cerebellum (Lammers et al., 1996) but their cellular distribution has ...

show abstract

The 5-Lipoxygenase as a Common Pathway for Pathological Brain and Vascular Aging

Cited by 34 publications

References 46 publications

Novel Key Players in the Development of Tau Neuropathology: Focus on the 5-Lipoxygenase

Novel Key Players in the Development of Tau Neuropathology: Focus on the 5-Lipoxygenase

The 5-Lipoxygenase as modulator of Alzheimer’s γ-secretase and therapeutic target

5-Lipoxygenase in mouse cerebellar Purkinje cells

Contact Info

Product

Resources

About