Alzheimer Disease: Farooqui AA

Farooqui AA, Ong WY, Horrocks LA, Chen P, Farooqui T. · Department of Molecular and Cellular Biochemistry, The Ohio State University, 1645 Neil Avenue, Columbus, OH 43210, USA. · Brain Res Rev. · Pubmed #17959252 No free full text.

Abstract: Neural membranes are composed of glycerophospholipids, sphingolipids, cholesterol and proteins. The distribution of these lipids within the neural membrane is not random but organized. Neural membranes contain lipid rafts or microdomains that are enriched in sphingolipids and cholesterol. These rafts act as platforms for the generation of glycerophospholipid-, sphingolipid-, and cholesterol-derived second messengers, lipid mediators that are necessary for normal cellular function. Glycerophospholipid-derived lipid mediators include eicosanoids, docosanoids, lipoxins, and platelet-activating factor. Sphingolipid-derived lipid mediators include ceramides, ceramide 1-phosphates, and sphingosine 1-phosphate. Cholesterol-derived lipid mediators include 24-hydroxycholesterol, 25-hydroxycholesterol, and 7-ketocholesterol. Abnormal signal transduction processes and enhanced production of lipid mediators cause oxidative stress and inflammation. These processes are closely associated with the pathogenesis of acute neural trauma (stroke, spinal cord injury, and head injury) and neurodegenerative diseases such as Alzheimer disease. Statins, the HMG-CoA reductase inhibitors, are effective lipid lowering agents that significantly reduce risk for cardiovascular and cerebrovascular diseases. Beneficial effects of statins in neurological diseases are due to their anti-excitotoxic, antioxidant, and anti-inflammatory properties. Fish oil omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have similar anti-excitotoxic, antioxidant and anti-inflammatory effects in brain tissue. Thus the lipid mediators, resolvins, protectins, and neuroprotectins, derived from eicosapentaenoic acid and docosahexaenoic acid retard neuroinflammation, oxidative stress, and apoptotic cell death in brain tissue. Like statins, ingredients of fish oil inhibit generation of beta-amyloid and provide protection from oxidative stress and inflammatory processes. Collective evidence suggests that antioxidant, anti-inflammatory, and anti-apoptotic properties of statins and fish oil contribute to the clinical efficacy of treating neurological disorders with statins and fish oil. We speculate that there is an overlap between neurochemical events associated with neural cell injury in stroke and neurodegenerative diseases. This commentary compares the neurochemical effects of statins with those of fish oil.

Farooqui AA, Horrocks LA, Farooqui T. · Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210, USA. · J Neurosci Res. · Pubmed #17393491 No free full text.

Abstract: The neural membranes contain phospholipids, sphingolipids, cholesterol, and proteins. Glycerophospholipids and sphingolipids are precursors for lipid mediators involved in signal transduction processes. Degradation of glycerophospholipids by phospholipase A(2) (PLA(2)) generates arachidonic acid (AA) and docosahexaenoic acids (DHA). Arachidonic acid is metabolized to eicosanoids and DHA is metabolized to docosanoids. The catabolism of glycosphingolipids generates ceramide, ceramide 1-phosphate, sphingosine, and sphingosine 1-phosphate. These metabolites modulate PLA(2) activity. Arachidonic acid, a product derived from glycerophospholipid catabolism by PLA(2), modulates sphingomyelinase (SMase), the enzyme that generates ceramide and phosphocholine. Furthermore, sphingosine 1-phosphate modulates cyclooxygenase, an enzyme responsible for eicosanoid production in brain. This suggests that an interplay and cross talk occurs between lipid mediators of glycerophospholipid and glycosphingolipid metabolism in brain tissue. This interplay between metabolites of glycerophospholipid and sphingolipid metabolism may play an important role in initiation and maintenance of oxidative stress associated with neurologic disorders as well as in neural cell proliferation, differentiation, and apoptosis. Recent studies indicate that PLA(2) and SMase inhibitors can be used as neuroprotective and anti-apoptotic agents. Development of novel inhibitors of PLA(2) and SMase may be useful for the treatment of oxidative stress, and apoptosis associated with neurologic disorders such as stroke, Alzheimer disease, Parkinson disease, and head and spinal cord injuries.

Farooqui AA, Horrocks LA. · Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, 43210, USA. · Neuroscientist. · Pubmed #16684969 No free full text.

Abstract: Phospholipase A2 (PLA2) generates arachidonic acid, docosahexaenoic acid, and lysophospholipids from neural membrane phospholipids. These metabolites have a variety of physiological effects by themselves and also are substrates for the synthesis of more potent lipid mediators such as eicosanoids, platelet activating factor, and 4-hydroxynonenal (4-HNE). At low concentrations, these mediators act as second messengers. They affect and modulate several cell functions, including signal transduction, gene expression, and cell proliferation, but at high concentrations, these lipid mediators cause neurotoxicity. Among the metabolites generated by PLA2, 4-HNE is the most cytotoxic metabolite and is associated with the apoptotic type of neural cell death. Levels of 4-HNE are markedly increased in neurological disorders such as Alzheimer disease, Parkinson disease, ischemia, spinal cord trauma, and head injury. The purpose of this review is to summarize and integrate the vast literature on metabolites generated by PLA2 for a wider audience. The authors hope that this discussion will jump-start more studies not only on the involvement of PLA2 in neurological disorders but also on the importance of PLA2-generated lipid mediators in physiological and pathological processes.

Ong WY, Farooqui AA. · Department of Anatomy, National University of Singapore, Singapore 119260. · J Alzheimers Dis. · Pubmed #16308487 No free full text.

Abstract: The present article reviews the roles and interactions of iron and neuroinflammation in Alzheimer's disease. It highlights the importance of neuroinflammatory changes in the glial scar after neuronal injury, in promoting iron accumulation, and iron-dependent oxidative damage. Elevation of iron in Alzheimer's disease not only affects amyloid precursor protein processing and mitochondrial function but also induces the aggregation of Abeta peptide and abnormalities in signal transduction processes associated with oxidative damage. Collective evidence suggests that although alterations in iron homeostasis may not be the primary triggering event that starts the pathological cascade of Alzheimer's disease, it is an important factor involved in neuroinflammation and progression of this disease.

Farooqui AA, Ong WY, Horrocks LA. · Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio 43210, USA. · Neurochem Res. · Pubmed #15662832 No free full text.

Abstract: Neural membrane phospholipids are hydrolyzed by a group of enzymes known as phospholipases. This process results in the generation of second messengers such as arachidonic acid, eicosanoids, platelet activating factor, and diacylglycerols. High levels of these metabolites are neurotoxic and are associated with neurodegeneration. The collective evidence from many studies suggests that neural membrane phospholipid metabolism is disturbed in neural trauma and neurodegenerative diseases. This disturbance is caused by the stimulation of phospholipases A2. Stimulation of these enzymes produces changes in membrane permeability, fluidity, and alteration in ion homeostasis. Low calcium influx produces mild oxidative stress and results in neurodegeneration promoted by apoptosis, whereas a calcium overload generates high oxidative stress and causes neurodegeneration associated with necrosis. Alterations in phospholipid metabolism along with the accumulation of lipid peroxides and compromised energy metabolism may be responsible for neurodegeneration in ischemia, spinal cord trauma, head injury, and Alzheimer disease. The synthesis of phospholipases A2 inhibitors that cross the blood-brain barrier without harm may be useful for the treatment of acute neural trauma and neurodegenerative diseases.

Farooqui AA, Antony P, Ong WY, Horrocks LA, Freysz L. · Department of Molecular and Cellular Biochemistry, The Ohio State University, 1645 Neil Ave, Columbus, OH 43210, USA. · Brain Res Brain Res Rev. · Pubmed #15210303 No free full text.

Abstract: Retinoic acid modulates a wide variety of biological processes including proliferation, differentiation, and apoptosis. It interacts with specific receptors in the nucleus, the retinoic acid receptors (RARs). The molecular mechanism by which retinoic acid mediates cellular differentiation and growth suppression in neural cells remains unknown. However, retinoic acid-induced release of arachidonic acid and its metabolites may play an important role in cell proliferation, differentiation, and apoptosis. In brain tissue, arachidonic acid is mainly released by the action of phospholipase A2 (PLA2) and phospholipase C (PLC)/diacylglycerol lipase pathways. We have used the model of differentiation in LA-N-1 cells induced by retinoic acid. The treatment of LA-N-1 cells with retinoic acid produces an increase in phospholipase A2 activity in the nuclear fraction. The pan retinoic acid receptor antagonist, BMS493, can prevent this increase in phospholipase A2 activity. This suggests that retinoic acid-induced stimulation of phospholipase A2 activity is a retinoic acid receptor-mediated process. LA-N-1 cell nuclei also have phospholipase C and phospholipase D (PLD) activities that are stimulated by retinoic acid. Selective phospholipase C and phospholipase D inhibitors block the stimulation of phospholipase C and phospholipase D activities. Thus, both direct and indirect mechanisms of arachidonic acid release exist in LA-N-1 cell nuclei. Arachidonic acid and its metabolites markedly affect the neurite outgrowth and neurotransmitter release in cells of neuronal and glial origin. We propose that retinoic acid receptors coupled with phospholipases A2, C and D in the nuclear membrane play an important role in the redistribution of arachidonic acid in neuronal and non-nuclear neuronal membranes during differentiation and growth suppression. Abnormal retinoid metabolism may be involved in the downstream transcriptional regulation of phospholipase A2-mediated signal transduction in schizophrenia and Alzheimer disease (AD). The development of new retinoid analogs with diminished toxicity that can cross the blood-brain barrier without harm and can normalize phospholipase A2-mediated signaling will be important in developing pharmacological interventions for these neurological disorders.

Horrocks LA, Farooqui AA. · Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH 43210, USA. · Prostaglandins Leukot Essent Fatty Acids. · Pubmed #15041028 No free full text.

Abstract: The central nervous system has the second highest concentration of lipids after adipose tissue. Long chain fatty acids, particularly arachidonic acid and docosahexaenoic acid, are integral components of neural membrane phospholipids. Alterations in neural membrane phospholipid components cannot only influence crucial intracellular and intercellular signaling but also alter many membrane physical properties such as fluidity, phase transition temperature, bilayer thickness, and lateral domains. A deficiency of docosahexaenoic acid markedly affects neurotransmission, membrane-bound enzyme and ion channel activities, gene expression, intensity of inflammation, and immunity and synaptic plasticity. Docosahexaenoic acid deficiency is associated with normal aging, Alzheimer disease, hyperactivity, schizophrenia, and peroxisomal disorders. Although the molecular mechanism of docosahexaenoic acid involvement in the disorders remains unknown, the supplementation of docosahexaenoic acid in the diet restores gene expression and modulates neurotransmission. Also, improvements are seen in signal transduction processes associated with behavioral deficits, learning activity, peroxisomal disorders, and psychotic changes in schizophrenia, depression, hyperactivity, stroke, and Alzheimer disease.

Farooqui AA, Ong WY, Horrocks LA. · Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio 43210, USA. · Adv Exp Med Biol. · Pubmed #14713251 No free full text.

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Farooqui AA, Horrocks LA. · Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus 43210-1218, USA. · Neuroscientist. · Pubmed #11499402 No free full text.

Abstract: Plasmalogens are unique glycerophospholipids because they have an enol ether double bond at the sn-1 position of the glycerol backbone. They are found in all mammalian tissues, with ethanolamine plasmalogens 10-fold higher than choline plasmalogens except in muscles. The enol ether double bond at the sn-1 position makes plasmalogens more susceptible to oxidative stress than the corresponding ester-bonded glycerophospholipids. Plasmalogens are not only structural membrane components and a reservoir for second messengers but may also be involved in membrane fusion, ion transport, and cholesterol efflux. Plasmalogens may also act as antioxidants, thus protecting cells from oxidative stress. Receptor-mediated degradation of plasmalogens by plasmalogen-selective phospholipase A2 results in the generation of arachidonic acid, eicosanoids, and platelet activating factor. Low levels of these metabolites have trophic effects, but at high concentration they are cytotoxic and may be involved in allergic response, inflammation, and trauma. Levels of plasmalogens are decreased in several neurological disorders including Alzheimer's disease, ischemia, and spinal cord trauma. This may be due to the stimulation of plasmalogen-selective phospholipase A2. A deficiency of plasmalogens in peroxisomal disorders and Niemann-Pick type C disease indicates that this deficiency may be due to the decreased activity of plasmalogen synthesizing enzymes that occur in peroxisomes.