Akhlaq A Farooqui

Publications (74)237.53 Total impact

• Article: Slow Excitotoxicity in Alzheimer's Disease.

  Wei-Yi Ong, Kazuhiro Tanaka, Gavin S Dawe, Lars M Ittner, Akhlaq A Farooqui
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  ABSTRACT: Progress is being made in identifying possible pathogenic factors and novel genes in the development of Alzheimer's disease (AD). Many of these could contribute to 'slow excitotoxicity', defined as neuronal loss due to hyperexcitation as a consequence of decreased energy production due, for instance, to changes in insulin receptor signaling; or receptor abnormalities, such as tau-induced alterations in the N-methyl-D-aspartate (NMDA) receptor phosphorylation. As a result, glutamate becomes neurotoxic at concentrations that normally show no toxicity. In AD, NMDA receptors are overexcited by glutamate in a tonic, rather than a phasic manner. Moreover, in prodromal AD subjects, functional MRI reveals an increase in neural network activities relative to baseline, rather than a loss of activity. This may be an attempt to compensate for reduced number of neurons, or reflect ongoing slow excitotoxicity. This article reviews possible links between AD pathogenic factors such as AβPP/Aβ and tau; novel risk genes including clusterin, phosphatidylinositol-binding clathrin assembly protein, complement receptor 1, bridging integrator 1, ATP-binding cassette transporter 7, membrane-spanning 4-domains subfamily A, CD2-associated protein, sialic acid-binding immunoglobulin-like lectin, and ephrin receptor A1; metabolic changes including insulin resistance and hypercholesterolemia; lipid changes including alterations in brain phospholipids, cholesterol, and ceramides; glial changes affecting microglia and astrocytes; alterations in brain iron metallome and oxidative stress; and slow excitotoxicity. Better understanding of the possible molecular links between pathogenic factors and slow excitotoxicity could inform our understanding of the disease, and pave the way toward new therapeutic strategies for AD.
  Journal of Alzheimer's disease: JAD 03/2013; · 3.74 Impact Factor
• Article: Brain lipid changes after repetitive transcranial magnetic stimulation: potential links to therapeutic effects?

  Lynette Hui-Wen Lee, Chay-Hoon Tan, Yew-Long Lo, Akhlaq A. Farooqui, Guanghou Shui, Markus R. Wenk, Wei-Yi Ong
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  ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) is increasingly used in the management of neurologic disorders such as depression and chronic pain, but little is known about how it could affect brain lipids, which play important roles in membrane structure and cellular functions. The present study was carried out to examine the effects of rTMS on brain lipids at the individual molecular species level using the novel technique of lipidomics. Rats were subjected to high frequency (15Hz) stimulation of the left hemisphere with different intensities and pulses of rTMS. The prefrontal cortex, hippocampus and striatum were harvested 1week after rTMS and lipid profiles analyzed by tandem mass spectrometry. rTMS resulted in changes mainly in the prefrontal cortex. There were significant alterations in plasmalogen phosphatidylethanolamines, phosphatidylcholines, and increases in sulfated galactosylceramides or sulfatides. Plasmalogen species with long chain polyunsaturated fatty acids (PUFAs) showed decrease in abundance together with corresponding increase in lysophospholipid species suggesting endogenous release of long chain fatty acids such as docosahexaenoic acid (DHA) in brain tissue. The hippocampus showed no significant changes, whilst changes in the striatum were often opposite to that of the prefrontal cortex. It is postulated that changes in brain lipids may underlie some of the clinical effects of rTMS. KeywordsTranscranial magnetic stimulation–Sulfatide–Plasmalogens–Lipids–Polyunsaturated fatty acids–Depression–Pain–Alzheimer’s disease–Frontal cortex
  Metabolomics 04/2012; 8(1):19-33. · 4.51 Impact Factor
• Article: Deacylation and reacylation of neural membrane glycerophospholipids

  Akhlaq A. Farooqui, Lloyd A. Horrocks, Tahira Farooqui
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  ABSTRACT: The deacylation-reacylation cycle is an important mechanism responsible for the introduction of polyunsaturated fatty acids into neural membrane glycerophospholipids. It involves four enzymes, namely acyl-CoA synthetase, acyl-CoA hydrolase, acyl-CoA: lysophospholipid acyltransferase, and phospholipase A2. All of these enzymes have been purified and characterized from brain tissue. Under normal conditions, the stimulation of neural membrane receptors by neurotransmitters and growth factors results in the release of arachidonic acid from neural membrane glycerophospholipids. The released arachidonic acid acts as a second messenger itself. It can be further metabolized to eicosanoids, a group of second messengers involved in a variety of neurochemical functions. A lysophospholipid, the second product of reactions catalyzed by phospholipase A2, is rapidly acylated with acyl-CoA, resulting in the maintenance of the normal and essential neural membrane glycerophospholipid composition. However, under pathological situations (ischemia), the overstimulation of phospholipase A2 results in a rapid generation and accumulation of free fatty acids including arachidonic acid, eicosanoids, and lipid peroxides. This results in neural inflammation, oxidative stress, and neurodegeneration. In neural membranes, the deacylation-reacylation cycle maintains a balance between free and esterified fatty acids, resulting in low levels of arachidonic acid and lysophospholipids. This is necessary for not only normal membrane integrity and function, but also for the optimal activity of the membrane-bound enzymes, receptors, and ion channels involved in normal signal-transduction processes.
  Journal of Molecular Neuroscience 04/2012; 14(3):123-135. · 2.50 Impact Factor
• Article: Distribution of calcium-independent phospholipase A2 (iPLA2) in monkey brain

  Wei-Yi Ong, Jin-Fei Yeo, Su-Fung Ling, Akhlaq A. Farooqui
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  ABSTRACT: The present study was carried out to elucidate the distribution of calcium-independent phospholipase A2 (iPLA2) in the normal monkey brain. iPLA2 immunoreactivity was observed in structures derived from the telencephalon, including the cerebral neocortex, amygdala, hippocampus, caudate nucleus, putamen, and nucleus accumbens, whereas structures derived from the diencephalon, including the thalamus, hypothalamus and globus pallidus were lightly labeled. The midbrain, vestibular, trigeminal and inferior olivary nuclei, and the cerebellar cortex were densely labeled. Immunoreactivity was observed on the nuclear envelope of neurons, and dendrites and axon terminals at electron microscopy. Western blot analysis showed higher levels of iPLA2 protein in the cytosolic, than the nuclear fraction, but little or no protein in the membrane fraction. Similarly, subcellular fractionation studies of iPLA2 activity in rat brain cortical cell cultures showed greater enzymatic activity in the cytosolic, than the nuclear fraction, and the least activity in non-nuclear membranes. The association of iPLA2 with the nuclear envelope suggests a role of the enzyme in nuclear signaling, such as during neuronal proliferation and differentiation or death. In addition, the localization of iPLA2 in dendrites and axon terminals suggests a role of the enzyme in neuronal signaling.
  Journal of Neurocytology 04/2012; 34(6):447-458. · 1.94 Impact Factor
• Article: Plasmalogens, phospholipase A2, and docosahexaenoic acid turnover in brain tissue

  Akhlaq A. Farooqui, Lloyd A. Horrocks
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  ABSTRACT: Plasmalogens are glycerophospholipids of neural membranes containing vinyl ether bonds. Their synthetic pathway is located in peroxisomes and endoplasmic reticulum. The rate-limiting enzymes are in the peroxisomes and are induced by docosahexaenoic acid (DHA). Plasmalogens often contain arachidonic acid (AA) or DHA at the sn-2 position of the glycerol moiety. The receptor-mediated hydrolysis of plasmalogens by cytosolic plasmalogen-selective phospholipase A2 generates AA or DHA and lysoplasmalogens. AA is metabolized to eicosanoids. The mechanism of signaling with DHA is not known. The plasmalogen-selective phospholipase A2 differs from other intracellular phospholipases A2 in molecular mass, kinetic properties, substrate specificity, and response to glycosaminoglycans, gangliosides, and sialoglycoproteins. A major portion of [3H]DHA incorporated into neural membranes is found at the sn-2 position of ethanolamine glycerophospholipids. Studies with a mutant cell line defective in plasmalogen biosynthesis indicate that the incorporation of DHA is reduced in this RAW 264.7 cell line by 50%. In contrast, the incorporation of AA remains unaffected. This is reversed completely when the growth medium is supplemented with sn-1-hexadecylglycerol, suggesting that DHA can be selectively targeted for incorporation into plasmalogens. We suggest that deficiencies of DHA and plasmalogens in peroxisomal disorders, Alzheimer’s disease (AD), depression, and attention deficit hyperactivity disorders (ADHD) may be responsible for abnormal signal transduction associated with learning disability, cognitive deficit, and visual dysfunction. These abnormalities in the signal-transduction process can be partially corrected by supplementation with a diet enriched with DHA.
  Journal of Molecular Neuroscience 04/2012; 16(2):263-272. · 2.50 Impact Factor
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  Available from: Tahira Farooqui

  Article: Metabolic syndrome as a risk factor for neurological disorders.

  Akhlaq A Farooqui, Tahira Farooqui, Francesco Panza, Vincenza Frisardi
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  ABSTRACT: The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. At the molecular level, metabolic syndrome is accompanied not only by dysregulation in the expression of adipokines (cytokines and chemokines), but also by alterations in levels of leptin, a peptide hormone released by white adipose tissue. These changes modulate immune response and inflammation that lead to alterations in the hypothalamic 'bodyweight/appetite/satiety set point,' resulting in the initiation and development of metabolic syndrome. Metabolic syndrome is a risk factor for neurological disorders such as stroke, depression and Alzheimer's disease. The molecular mechanism underlying the mirror relationship between metabolic syndrome and neurological disorders is not fully understood. However, it is becoming increasingly evident that all cellular and biochemical alterations observed in metabolic syndrome like impairment of endothelial cell function, abnormality in essential fatty acid metabolism and alterations in lipid mediators along with abnormal insulin/leptin signaling may represent a pathological bridge between metabolic syndrome and neurological disorders such as stroke, Alzheimer's disease and depression. The purpose of this review is not only to describe the involvement of brain in the pathogenesis of metabolic syndrome, but also to link the pathogenesis of metabolic syndrome with neurochemical changes in stroke, Alzheimer's disease and depression to a wider audience of neuroscientists with the hope that this discussion will initiate more studies on the relationship between metabolic syndrome and neurological disorders.
  Cellular and Molecular Life Sciences CMLS 03/2012; 69(5):741-62. · 6.57 Impact Factor
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  Available from: Tahira Farooqui

  Article: Beneficial effects of propolis on human health and neurological diseases.

  Tahira Farooqui, Akhlaq A Farooqui
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  ABSTRACT: Propolis is a natural product, collected by honeybees Apis mellifera, from various plant sources. Propolis is extensively used in foods and beverages because it improves human health. It contains more than 300 natural compounds such as polyphenols, phenolic aldehydes, sequiterpene-quinones, coumarins, amino acids, steroids and inorganic compounds. Propolis exhibits a broad spectrum of biological and pharmacological properties such as antimicrobial, antioxidant, anti-inflammatory, immunomodulatory, antitumor, anticancer, antiulcer, hepatoprotective, cardioprotective, and neuroprotective actions. The chemical composition and beneficial properties of propolis vary greatly depending on the phytogeographical areas, seasonal collection time, and botanical source. Polyphenols found in fruits and vegetables are beginning to receive increased attention due to their vital role in protecting neural cells from oxidative stress and neuroinflammation associated with normal aging and chronic age-related diseases. Propolis is one of the most abundant sources of polyphenols (mainly flavonoids and phenolic acids). This overview is an attempt to discuss the molecular mechanism underlying the potential beneficial effects of propolis on human health and neurological diseases.
  Frontiers in bioscience (Elite edition) 01/2012; 4:779-93.
• Article: Kainate receptors mediate regulated exocytosis of secretory phospholipase A(2) in SH-SY5Y neuroblastoma cells.

  Aung Than, Yan Tan, Wei-Yi Ong, Akhlaq A Farooqui, Peng Chen
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  ABSTRACT: Secretory phospholipase A(2) (sPLA(2)) isoforms are widely expressed in the brain and spinal cord. Group IIA sPLA(2) (sPLA(2)-IIA) has been shown to stimulate exocytosis and release of neurotransmitters in neuroendocrine PC12 cells and neurons, suggesting a role of the enzyme in neuronal signaling and synaptic transmission. However, the mechanisms by which sPLA(2) is itself released, and a possible relation between glutamate receptors and sPLA(2) exocytosis, are unknown. This study was carried out to elucidate the effects of glutamate receptor agonists on exocytosis of sPLA(2)-IIA in transfected SH-SY5Y neuroblastoma cells. sPLA(2)-IIA enzyme was packaged in fusion-competent vesicles and released constitutively or upon stimulation, suggesting regulated secretion. The signal peptide of sPLA(2)-IIA is required for its vesicular localization and exocytosis. External application of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) induced vesicular exocytosis and release of sPLA(2)-IIA. UBP 302, a GluR5-specific KA receptor antagonist, abolished the effect of KA, confirming the role of KA receptors in mediating sPLA(2)-IIA secretion. Moreover, KA-induced sPLA(2)-IIA secretion is dependent on Ca(2+) and protein kinase C. Together, these findings provide evidence of a link between glutamate receptors and regulated sPLA(2) secretion in neurons that may play an important role in synaptic plasticity, pain transmission and neurodegenerative diseases.
  Neurosignals 10/2011; 20(2):72-85. · 2.11 Impact Factor
• Article: Lipid mediators and their metabolism in the nucleous: implications for Alzheimer's disease.

  Akhlaq A Farooqui
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  ABSTRACT: Lipid mediators are important endogenous regulators derived from enzymatic degradation of glycerophospholipids, sphingolipids, and cholesterol by phospholipases, sphingomyelinases, and cytochrome P450 hydroxylases, respectively. In neural cells, lipid mediators are associated with proliferation, differentiation, oxidative stress, inflammation, and apoptosis. A major group of lipid mediators, which originates from the enzymatic oxidation of arachidonic acid, is called eicosanoids (i.e., prostaglandins, leukotrienes, thromboxanes, and lipoxins). The corresponding lipid mediators of docosahexaenoic acid metabolism are named as docosanoids. They include resolvins, protectins (neuroprotectins), and maresins. Docosanoids produce antioxidant, anti-inflammatory, and antiapoptotic effects in brain tissue. Other glycerophospholipid-derived lipid mediators are platelet activating factor, lysophosphatidic acid, and endocannabinoids. Degradation of sphingolipids also results in the generation of sphingolipid-derived lipid mediators, such as ceramide, ceramide 1-phosphate, sphingosine, and sphingosine 1-phosphate. These mediators are involved in differentiation, growth, cell migration, and apoptosis. Similarly, cholesterol-derived lipid mediators, hydroxycholesterol, produce apoptosis. Abnormal metabolism of lipid mediators may be closely associated with pathogenesis of Alzheimer's disease.
  Journal of Alzheimer's disease: JAD 09/2011; 30 Suppl 2:S163-78. · 3.74 Impact Factor
• Article: Late-life depression and Alzheimer's disease: the glutamatergic system inside of this mirror relationship.

  Vincenza Frisardi, Francesco Panza, Akhlaq A Farooqui
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  ABSTRACT: Late-life depressive syndromes often arise in the context of predementia, dementia syndromes, and Alzheimer's disease (AD). Conversely, patients with a history of mood disorders are at higher risk of developing cognitive impairment. The high rate of co-occurrence of these two disorders is becoming a major health problem in older subjects for both their epidemiological impact and the negative outcomes in terms of disability and increased mortality. In this perspective, it is possible to speculate on the presence of a mirror relationship between depressive and cognitive disorders in late-life. Indeed, although a causal contribution of genetic, environmental, and social factors is widely recognized in these disorders, the neurobiological links still remain largely unknown. l-glutamic acid and γ-aminobutyric acid are the principal excitatory and inhibitory neurotransmitters in the central nervous system, respectively, and increasing evidence suggests that alterations in this neurotransmitter system may contribute to the neurobiology linking depression and cognitive impairment. In the present review article, we examined the neurobiological bases of the relationship between late-life depressive syndromes and AD, with a particular attention to glutamatergic pathway signalling like a bridge connecting these two conditions. In addition, attempts have been made to explain changes in glutamatergic pathway, depression in older age, and dementia through the analysis of signal transduction mechanisms associated with these disabling disorders.
  Brain Research Reviews 06/2011; 67(1-2):344-55. · 10.34 Impact Factor
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  Available from: Tahira Farooqui

  Article: Glycerophospholipids and glycerophospholipid-derived lipid mediators: a complex meshwork in Alzheimer's disease pathology.

  Vincenza Frisardi, Francesco Panza, Davide Seripa, Tahira Farooqui, Akhlaq A Farooqui
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  ABSTRACT: An increasing body of evidence suggested that intracellular lipid metabolism is dramatically perturbed in various cardiovascular and neurodegenerative diseases with genetic and lifestyle components (e.g., dietary factors). Therefore, a lipidomic approach was also developed to suggest possible mechanisms underlying Alzheimer's disease (AD). Neural membranes contain several classes of glycerophospholipids (GPs), that not only constitute their backbone but also provide the membrane with a suitable environment, fluidity, and ion permeability. In this review article, we focused our attention on GP and GP-derived lipid mediators suggested to be involved in AD pathology. Degradation of GPs by phospholipase A(2) can release two important brain polyunsaturated fatty acids (PUFAs), e.g., arachidonic acid and docosahexaenoic acid, linked together by a delicate equilibrium. Non-enzymatic and enzymatic oxidation of these PUFAs produces several lipid mediators, all closely associated with neuronal pathways involved in AD neurobiology, suggesting that an interplay among lipids occurs in brain tissue. In this complex GP meshwork, the search for a specific modulating enzyme able to shift the metabolic pathway towards a neuroprotective role as well as a better knowledge about how lipid dietary modulation may act to slow the neurodegenerative processes, represent an essential step to delay the onset of AD and its progression. Also, in this way it may be possible to suggest new preventive or therapeutic options that can beneficially modify the course of this devastating disease.
  Progress in lipid research 06/2011; 50(4):313-30. · 10.67 Impact Factor
• Article: Role of calcium independent phospholipase A2 in maintaining mitochondrial membrane potential and preventing excessive exocytosis in PC12 cells.

  May-Thu Ma, Jin-Fei Yeo, Akhlaq A Farooqui, Wei-Yi Ong
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  ABSTRACT: This study was carried out to elucidate the effects of calcium independent phospholipase A(2) (iPLA(2)) on mitochondrial function and exocytosis in neuroendocrine cells. iPLA(2) mRNA and protein were detected in cell lysates and mitochondria from PC12 cells. Treatment of cells with the iPLA(2) inhibitor, bromoenol lactone (BEL), resulted in reduction in the mitochondrial membrane potential. Increase in membrane capacitance and number of spikes at amperometry, indicating exocytosis, were detected from PC12 cells after treatment with BEL. The induced exocytosis was abolished by pre-incubation of cells with the antioxidant, glutathione monoethyl ester, spin-trap/free radical scavenger, PBN, or inhibitors of the mitochondrial permeability transition pore, cyclosporine A and bongkrekic acid. These findings indicate that inhibition of iPLA(2) results in excessive exocytosis through increased oxidative damage (or failure to repair such damage) and defects in mitochondrial function. A similar process may occur in neurons with mutations in iPLA(2), leading to neuronal injury.
  Neurochemical Research 02/2011; 36(2):347-54. · 2.24 Impact Factor
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  Available from: Tahira Farooqui

  Article: Lipid-mediated oxidative stress and inflammation in the pathogenesis of Parkinson's disease.

  Tahira Farooqui, Akhlaq A Farooqui
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  ABSTRACT: Parkinson's disease (PD) is a neurodegenerative movement disorder of unknown etiology. PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, depletion of dopamine in the striatum, abnormal mitochondrial and proteasomal functions, and accumulation of α-synuclein that may be closely associated with pathological and clinical abnormalities. Increasing evidence indicates that both oxidative stress and inflammation may play a fundamental role in the pathogenesis of PD. Oxidative stress is characterized by increase in reactive oxygen species (ROS) and depletion of glutathione. Lipid mediators for oxidative stress include 4-hydroxynonenal, isoprostanes, isofurans, isoketals, neuroprostanes, and neurofurans. Neuroinflammation is characterized by activated microglial cells that generate proinflammatory cytokines, such as TNF-α and IL-1β. Proinflammatory lipid mediators include prostaglandins and platelet activating factor, together with cytokines may play a prominent role in mediating the progressive neurodegeneration in PD.
  Parkinson's disease. 01/2011; 2011:247467.
• Article: Molecular Mechanism Underlying the Therapeutic Activities of Propolis: A Critical Review

  Tahira Farooqui, Akhlaq A. Farooqui
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  ABSTRACT: Propolis, a resinous bee-hive product referred as “bee glue”, is collected from various plant sources, such as buds of conifer and poplar trees, by honeybees (Apis mellifera). Honeybees blend this resinous non-toxic substance with their salivary secretions and wax flakes secreted from special glands on their abdomens. Propolis has been used as a healing agent for thousands of years in folk medicine. There is substantial evidence indicating that propolis exhibits a broad spectrum of therapeutic (biological/pharmacological) properties such as antimicrobial, anti-oxidant, anti-inflammatory, immunomodulatory, antitumor, anticancer, anti-ulcer, hepatoprotective, and cardioprotective properties. Propolis contains more than 200-300 natural compounds. The biological/pharmacological activities of propolis depend on the presence of a large number of polyphenols, mainly flavonoids (flavonoid aglycones), aromatic acids, phenolic acid esters (caffeates and ferulates), triterpenes, diterpenic acids and lignanes. The chemical composition and beneficial properties of propolis vary depending on the plant source, geographic origin and collection time. Present overview is an attempt to discuss the molecular mechanism(s) underlying the diverse biological effects of propolis.
  Current Nutrition & Food Science 07/2010; 6(3):186-199.
• Article: Studies on plasmalogen-selective phospholipase A2 in brain.

  Akhlaq A Farooqui
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  ABSTRACT: Plasmalogen-selective phospholipase A(2) (PlsEtn-PLA(2)) has been purified from pig brain using multiple column chromatographic procedure. The purified enzyme migrates as a single band on polyacrylamide. It is stimulated by Triton X-100 and inhibited by sodium deoxycholate. Purified PlsEtn-PLA(2) is inhibited by iodoacetate, and this inhibition can be prevented by beta-meracaptoethanol. Treatment of neuronal cell cultures with kainic acid stimulates PlsEtn-PLA(2) activity in a dose-dependent manner, and this stimulation can be blocked by Ly294486, a selective kainic acid receptor antagonist. Activities of PlsEtn-PLA(2) are markedly increased in plasma membrane and synaptosomal plasma membrane fraction prepared from nucleus basalis and hippocampal region of brains from Alzheimer disease patients compared to age-matched controls. It is proposed that accumulation of ceramide and increased expression of cytokines may be responsible for the stimulation of PlsEtn-PLA(2) in Alzheimer disease.
  Molecular Neurobiology 06/2010; 41(2-3):267-73. · 5.74 Impact Factor
• Article: Effects of cholesterol oxidation products on exocytosis.

  May-Thu Ma, Jing Zhang, Akhlaq A Farooqui, Peng Chen, Wei-Yi Ong
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  ABSTRACT: Increase in levels of oxysterols or cholesterol oxidation products have been detected in brain areas undergoing neuroinflammation after excitotoxic injury, and the present study was carried out to elucidate possible effects of these products on exocytosis in rat pheochromocytoma-12 (PC12) cells. An increase in vesicle fusion with the cell membrane indicating exocytosis was observed by total internal reflection microscopy (TIRFM), and confirmed by capacitance measurements, after addition of 7 ketocholesterol, 24 hydroxycholesterol or cholesterol 5, 6 beta epoxide. 7 ketocholesterol induced exocytosis was attenuated by pretreatment with a disruptor of cholesterol-rich domains or "lipid rafts", methyl-beta-cyclodextrin (MbetaCD) as demonstrated by capacitance and amperometry measurements of neurotransmitter release. Moreover, treatment of cells with thapsigargin to deplete intracellular calcium, or treatment of cells with lanthanum chloride to block calcium channels resulted in attenuation of 7 ketocholesterol induced exocytosis. Fura-2 imaging showed that 7 ketocholesterol induced rapid and sustained increases in intracellular calcium concentration, and that this effect was attenuated in cells that were pre-treated with MbetaCD, thapsigargin or lanthanum chloride. Together, the results suggest that neurotransmitter release triggered by 7 ketocholesterol is dependent on the integrity of cholesterol rich lipid domains on cellular membranes and a rise in intracellular calcium, either through release from internal stores or influx via calcium channels. Increased cholesterol oxidation product concentrations in brain areas undergoing neuroinflammation may enhance exocytosis and neurotransmitter release, thereby aggravating excitotoxicity.
  Neuroscience Letters 04/2010; 476(1):36-41. · 2.11 Impact Factor
• Article: Differential effects of lysophospholipids on exocytosis in rat PC12 cells.

  May-Thu Ma, Jin-Fei Yeo, Akhlaq A Farooqui, Jing Zhang, Peng Chen, Wei-Yi Ong
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  ABSTRACT: Secretory phospholipase A2 (sPLA2) activity is present in the CNS and the sPLA2-IIA isoform has been shown to induce exocytosis in cultured hippocampal neurons. However, little is known about possible contributions of various lysophospholipid species to exocytosis in neuroendocrine cells. This study was therefore carried out to examine the effects of several lysophospholipid species on exocytosis on rat pheochromocytoma-12 (PC12) cells. An increase in vesicle fusion, indicating exocytosis, was observed in PC12 cells after external infusion of lysophosphatidylinositol (LPI), but not lysophosphatidylcholine or lysophosphatidylserine by total internal reflection microscopy. Similarly, external infusion of LPI induced significant increases in capacitance, or number of spikes detected at amperometry, indicating exocytosis. Depletion of cholesterol by pre-incubation of cells with methyl beta cyclodextrin and depletion of Ca2+ by thapsigargin and incubation in zero external Ca2+ resulted in attenuation of LPI induced exocytosis, indicating that exocytosis was dependent on the integrity of lipid rafts and intracellular Ca2+. Moreover, LPI induced a rise in intracellular Ca2+ suggesting that this could be the trigger for exocytosis. It is postulated that LPI may be an active participant in sPLA2-mediated exocytosis in the CNS.
  Acta Neurovegetativa 03/2010; 117(3):301-8. · 2.73 Impact Factor
• Article: Changes in brain cholesterol metabolome after excitotoxicity.

  Wei-Yi Ong, Ji-Hyun Kim, Xin He, Peng Chen, Akhlaq A Farooqui, Andrew M Jenner
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  ABSTRACT: Excitotoxicity due to excess stimulation of glutamate receptors in neurons is accompanied by increased Ca(2+) influx, stimulation of Ca(2+)-dependent enzymes, ATP depletion, increase in lipid peroxidation products, and loss of glutathione. These changes resemble neurochemical alterations in acute neuronal injury (stroke, spinal cord injury, and traumatic brain injury) and chronic neurodegenerative diseases such as Alzheimer's disease. Intracerebroventricular injection of the potent glutamate analog kainate in rats results in increased cholesterol concentration in the hippocampus at short to medium time intervals, i.e., 3 days-1 week post-injection, as detected by gas chromatography-mass spectrometry in the lesioned hippocampus. This is accompanied by an early increase in levels of cholesterol biosynthetic precursors and increases in both enzymatically derived oxysterols such as 24-hydroxycholesterol and cholesterol oxidation products (COPs) generated by reactive oxygen species, including cholesterol epoxides and 7-ketocholesterol. In contrast to COPs, no change in concentration of the neurosteroid pregnenolone was found after KA injury. Cholesterol and COPs significantly increase exocytosis in cultured PC12 cells and neurons, and both oxysterols and COPs are able to induce cytotoxic and apoptotic injuries in different cell types, including neurons. Together, the findings suggest that increased cholesterol and COPs after KA excitotoxicity could themselves lead to disturbed neuronal ion homeostasis, increased neurotransmitter release, and propagation of excitotoxicity.
  Molecular Neurobiology 02/2010; 41(2-3):299-313. · 5.74 Impact Factor
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  Available from: Tahira Farooqui

  Article: Lipid mediators in the nucleus: Their potential contribution to Alzheimer's disease.

  Akhlaq A Farooqui, Wei-Yi Ong, Tahira Farooqui
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  ABSTRACT: Degradation of glycerophospholipids, sphingolipids and cholesterol in the nucleus modulates neural cell proliferation and differentiation, inflammation, apoptosis, migration, cell adhesion, and intracellular trafficking. Extracellular signals from agonists (neurotransmitters, cytokines, and growth factors) regulate the activity of a key set of lipid-metabolizing enzymes, such as phospholipases, sphingomyelinases, and cholesterol hydroxylases. These enzymes and their downstream targets constitute a complex lipid signaling network with multiple nodes of interaction and cross-regulation through their lipid mediators, which include eicosanoids, docosanoids, diacylglycerols, platelet activating factor, lysophosphatidic acid, ceramide and ceramide 1-phosphate, sphingosine and sphingosine 1-phosphate, and hydroxycholesterols. Receptors for above lipid mediators are localized at the neural cell nucleus. Stimulation of isolated nuclei with these lipids and agonists results in changes in transcriptional regulation of major genes, including c-fos, cylooxygenase-2, secretory phospholipase A(2) and endothelial as well as inducible nitric oxide synthases. Imbalances in signaling network involving above genes may contribute to the pathogenesis of human neurological disorders. In this review, we have attempted to integrate available information on above lipid mediators in the nucleus. In addition, attempts have been made to explain cross-talk among glycerophospholipid-, sphingolipid-, and cholesterol-derived lipid mediators in neural cell death in Alzheimer's disease.
  Biochimica et Biophysica Acta 02/2010; 1801(8):906-16. · 4.66 Impact Factor
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  Available from: Andrew Jenner

  Article: Changes in cholesterol biosynthetic and transport pathways after excitotoxicity.

  Ji-Hyun Kim, Jinatta Jittiwat, Wei-Yi Ong, Akhlaq A Farooqui, Andrew M Jenner
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  ABSTRACT: The present study was carried out to elucidate changes in the gene expression and activity of cholesterol biosynthetic enzymes and transporters in the rat hippocampus after kainate excitotoxicity. Significantly increased cholesterol level was detected in the degenerating hippocampus, reaching double normal levels at 1 week after kainate injury. RT-PCR analyses of hippocampal homogenates showed significantly decreased mRNA expression of the transcription factor controlling cholesterol biosynthesis SREBP-2, and the rate-controlling enzyme HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase at all time points after kainate injection; and decreased lanosterol synthase and CYP51 at 1 and 2 weeks post-kainate injection respectively. GC-MS analyses showed a significant increase in cholesterol biosynthetic precursors lanosterol, desmosterol and 7-dehydrocholesterol at 1 day after kainate injection presumably reflecting biosysnthesis in injured neurons, and significant decreases in precursors at 1 and 2 weeks post-kainate injection, at time of gliosis in the degenerating hippocampus. Levels of cholesterol autooxidation including 7 ketocholesterol and cholesterol epoxides were elevated in the kainate lesioned hippocampus. Furthermore, loss of expression of the cholesterol transporter, ABCA1 was detected in neurons, but increased expression in astrocytes was detected after kainate lesions. The results suggest that increased cholesterol biosynthesis and loss of ABCA1 expression in injured neurons might result in increase in cholesterol in the degenerating hippocampus. The increased cholesterol might predispose to increased formation of cholesterol oxidation products which have been shown to be toxic to neurons.
  Journal of Neurochemistry 10/2009; 112(1):34-41. · 4.06 Impact Factor