Glycerophospholipids and glycerophospholipid-derived lipid mediators: A complex meshwork in Alzheimer’s disease pathology

Frisardi, Vincenza; Panza, Francesco; Seripa, Davide; Farooqui, Tahira; Farooqui, Akhlaq A.

doi:10.1016/j.plipres.2011.06.001

Cited by 182 publications

(128 citation statements)

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“…For example, AA can be metabolized to infl ammatory eicosanoids via cyclooxygenases to yield prostaglandins and thromboxanes or via lipoxygenases to yield leukotrienes ( 34 ). By contrast, DHA can be metabolized to the anti-infl ammatory docosanoids via lipoxygenase enzymes to yield D-series resolvins and other neuroprotective compounds (e.g., neuroprotectin D1) ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Novel function of vitamin E in regulation of zebrafish (Danio rerio) brain lysophospholipids discovered using lipidomics

Choi

Leonard

Kasper

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org have used zebrafi sh to characterize the molecular consequences of vitamin E defi ciency because zebrafi sh require dietary ␣ -tocopherol, especially during embryonic development ( 2 ). Zebrafi sh also express the ␣ -tocopherol transfer protein ( ␣ -TTP), which facilitates hepatic ␣ -tocopherol secretion into the circulation in humans ( 3 ), and likely facilitates ␣ -tocopherol delivery from the yolk to the developing zebrafi sh embryo ( 4 ). Importantly, when the ␣ -TTP was knocked down in zebrafi sh embryos by 12-15 h postfertilization, the embryonic brain and eyes failed to form appropriately ( 4 ), indicating that ␣ -tocopherol is necessary for nervous system development. Further, during embryonic growth over 72 h both DHA (22:6) and arachidonic acid (AA) (20:4) decreased at faster rates in vitamin E-defi cient (E Ϫ ) compared with vitamin E-suffi cient (E+) zebrafi sh embryos ( 5 ). Moreover, adequate dietary ascorbic acid was necessary to prevent accelerated ␣ -tocopherol defi ciency and tissue damage ( 5 ).We hypothesized that the devastating effects of severe ␣ -tocopherol defi ciency in zebrafi sh embryos ( 4 ) are a result of depletion and alteration of critical brain lipids. Hypothetically, the brain, which is highly enriched in DHA yet cannot synthesize DHA to meet its needs ( 6 ), is highly susceptible to lipid peroxidation in the ␣ -tocopheroldefi cient state. It has been recognized for decades in humans that vitamin E defi ciency causes a progressive spinocerebellar ataxia ( 7 ). Moreover, Ulatowski et al. ( 8 ) have shown that vitamin E is necessary for preservation of Abstract We hypothesized that brains from vitamin E-defi cient (E ؊ ) zebrafi sh ( Danio rerio ) would undergo increased lipid peroxidation because they contain highly polyunsaturated fatty acids, thus susceptible lipids could be identifi ed. Brains from zebrafi sh fed for 9 months defi ned diets without (E ؊ ) or with (E+) added vitamin E (500 mg RRR -␣ -tocopheryl acetate per kilogram diet) were studied. Using an untargeted approach, 1-hexadecanoyl-2-docosahexaenoyl-sn -glycero-3-phosphocholine [DHA-PC 38:6, PC 16:0/22:6]was the lipid that showed the most signifi cant and greatest fold-differences between groups. DHA-PC concentrations were approximately 1/3 lower in E ؊ (4.3 ± 0.6 mg/g) compared with E+ brains (6.5 ± 0.9 mg/g, mean ± SEM, n = 10 per group, P = 0.04). Using lipidomics, 155 lipids in brain extracts were identifi ed. Only four phospholipids (PLs) were different ( P < 0.05) between groups; they were lower in E ؊ brains and contained DHA with DHA-PC 38:6 at the highest abundances. Moreover, hydroxy-DHA-PC 38:6 was increased in E ؊ brains ( P = 0.0341) supporting the hypothesis of DHA peroxidation. More striking was the depletion in E ؊ brains of nearly 60% of 19 different lysophospholipids (lysoPLs) (combined P = 0.0003), which are critical for membrane PL remodeling. Thus, E ؊ brains contained fewer DHA-PLs, more hydroxy-DHA-PCs, and fewer lysoPLs, suggesting t...

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Section: Discussionmentioning

confidence: 99%

Novel function of vitamin E in regulation of zebrafish (Danio rerio) brain lysophospholipids discovered using lipidomics

Choi

Leonard

Kasper

et al. 2015

Journal of Lipid Research

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“…The increase of these pro-inflammatory mediators in brain and biofluids has been repeatedly described in both human AD Trushina et al, 2013) and transgenic models (Piro et al, 2012;Lin et al, 2013;Lin et al, 2014). This inflammatory process has been traditionally associated with the overactivation of phospholipases, principally PLA 2 , leading to the release of polyunsaturated fatty acids from the hydrolysis of phospholipids , and subsequent oxidation by cyclooxygenases and 5-lipoxygenase (Manev et al, 2011), generating a complex meshwork of lipid mediators closely associated with neuronal pathways involved in AD neurobiology (Frisardi et al, 2011). However no substantial differences were observed between the APP/PS1 and APP/PS1/IL4 mice ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic research on the role of interleukin-4 in Alzheimer’s disease

et al. 2015

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Abstract:Inflammation plays a prominent role in the pathogenesis of Alzheimer's disease, affecting both brain and the peripheral system. Thus, modulation of inflammation in animal models of this neurodegenerative disorder may be of great interest to elucidate the pathological mechanisms underlying this inflammatory component. To this end, a metabolomic investigation on a triple transgenic mouse model obtained by crossing the APP/PS1 mice with interleukin-4 knockout mice (a model of impaired immune function) was performed for the first time. Serum samples from transgenic mice and wild type animals were analyzed by direct infusion mass spectrometry followed by multivariate statistics in order to identify altered metabolites. Subsequently, metabolic pathway analysis allowed the elucidation of potential pathological mechanisms associated with the development of Alzheimer-type disorders in response to interleukin-4 deficiency, such as impaired homeostasis of histamine, altered metabolism of amino acids (threonine, aspartate and tyrosine), deregulated urea cycle and increased production of eicosanoids. Therefore, this work demonstrates the potential of this triple transgenic model with modulated immunity for the study of pathological mechanisms associated with inflammation in Alzheimer's disease. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation COMMENTS FOR THE AUTHOR:Reviewer #1: The authors have not included some important requests for clarification to be added to the manuscript by the reviewer therefor another minor revision is required. Abstract still poorly writtenFor example this sentence:Thereby, the investigation of this inflammatory component presents a great potential for the elucidation of pathological mechanisms underlying to disease, the discovery of potential markers of diagnosis and the development of novel therapeutic approaches Abstract was rewritten. Authors commentWe did not use internal standards because we considered that the validation of reproducibility in metabolomic methods is better assessed using QC samples. In this sense, Naz et al. recently described that "although spiking some selected metabolites could give a good approach to the general behaviour of the method, results cannot be assumed for all the components in the sample" (J Chromatogr A 2014;1353:99). Instead, biological QCs show a similar composition to real samples, so they are preferable for validating non-targeted approaches. Thus, "the se of QCs in non-targeted metabolomics analysis can be considered as equivalent to the use of standards in routine target analysis". Reviewer comment: I don't agree with this statement how can you account for a one off issue and internal standards are also in the sample matrix. You need add this justification to the manuscriptInternal standards must present similar physico-chemical properties to the chemical species of interest in the sample. However, metabolomics approaches are not focused on individual compounds, so the use of internal standards in these method...

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“…GPs and sphingolipids are not only essential for the structural integrity of neuronal membranes, but also serve as precursors of bioactive lipid mediators in the brain [28] . GPs bind membrane proteins to help them maintain a proper position and tight integration in the lipid bilayer.…”

Section: Major Lipid Classes and Functions In The Brainmentioning

confidence: 99%

“…Cholesterol depletion in neurons impairs synaptic vesicle exocytosis, neuronal activity, and neurotransmission, and leads to dendritic spine and synapse degeneration [21][22][23] . Abnormal cholesterol metabolism is associated with many neurodegenerative diseases such as Niemann-Pick C disease, Huntington's disease, AD, and Parkinson's disease [24][25][26][27] .GPs and sphingolipids are not only essential for the structural integrity of neuronal membranes, but also serve as precursors of bioactive lipid mediators in the brain [28] . GPs bind membrane proteins to help them maintain a proper position and tight integration in the lipid bilayer.…”

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confidence: 99%

Lipid metabolism in Alzheimer’s disease

Liu

Zhang

2014

Neurosci. Bull.

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Lipids play crucial roles in cell signaling and various physiological processes, especially in the brain. Impaired lipid metabolism in the brain has been implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), and other central nervous system insults. The brain contains thousands of lipid species, but the complex lipid compositional diversity and the function of each of lipid species are currently poorly understood. This review integrates current knowledge about major lipid changes with the molecular mechanisms that underlie AD pathogenesis. Keywords: brain aging; lipid metabolism; Alzheimer's disease ·Review· IntroductionLipids are abundant in the brain. These lipids consist of glycerophospholipids (GPs), sphingolipids, and cholesterol in roughly equimolar proportions [1] . The brain contains about 20% of the total body cholesterol [2] . Cholesterol is primarily derived from local synthesis, whereas uptake of lipoprotein particle-derived cholesterol from the peripheral circulation is usually prevented by the blood-brain-barrier. Lipids, especially cholesterol, have recently been extensively studied in many neurodegenerative diseases. Impairment of cholesterol metabolism (synthesis, transport, and utilization by neurons) in the brain is linked to Alzheimer's disease (AD) and the aging process. In addition, lipid oxidation products accumulate at high levels in aging tissues in mice [3] . Recent studies have demonstrated the important role of altered metabolism in AD [4] . Sphingomyelinases promote apoptosis in human primary neurons through the generation of a proapoptotic molecule, ceramide [5] .Moreover, upregulated arachidonic acid metabolism has been reported in hAPP-J20 AD mice as well as in the AD brain, particularly in regions having high densities of senile plaques with activated microglia [6,7] . Although the potential link between cholesterol and AD pathogenesis has been intensively studied, growing evidence suggests that other lipids, such as sphingolipids and GPs, also play an important role. Here, we review some recent advances in understanding the role lipids play in the aging process and AD pathogenesis. Major Lipid Classes and Functions in the BrainAlthough most lipids serve as structural lipids in cell membranes, they are also directly involved in membrane trafficking, intracellular architecture, and the regulation of proteins and sub-compartments in membranes (lipid rafts) (Table 1). Eukaryotic organisms might contain a dozen major lipid classes, each comprising hundreds of individual molecular species [8] . Lipids have the potential to generate 9 000-100 000 molecular species [9,10] , and a mammalian cell may contain 1 000-2 000 [11] . The brain is one of the most lipid-enriched organs, containing several major classes, such as cholesterol, GPs, sphingolipids and fatty acids [12] . The biological significance of the compositional complexity of lipids is poorly understood. However, the recent development of the shot-gun lipidomics technique may provide more sensitive and quant...

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Glycerophospholipids and glycerophospholipid-derived lipid mediators: A complex meshwork in Alzheimer’s disease pathology

Cited by 182 publications

References 248 publications

Novel function of vitamin E in regulation of zebrafish (Danio rerio) brain lysophospholipids discovered using lipidomics

Novel function of vitamin E in regulation of zebrafish (Danio rerio) brain lysophospholipids discovered using lipidomics

Metabolomic research on the role of interleukin-4 in Alzheimer’s disease

Lipid metabolism in Alzheimer’s disease

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