Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phospholipase A(2) (E.C. 3.1.1.4, PLA(2)) plays an essential role in metabolism of membrane phospholipids, it is related to inflammatory reactions, secretion of amyloid precursor protein and activation of NMDA receptor after ischemia. In the present study we investigated PLA(2) activity in platelets from 37 Alzheimer's disease (AD) patients, 32 vascular dementia (VaD) patients and 32 individuals with ischemic stroke as compared to 27 healthy elderly controls. PLA(2) activity was determined using radiometric assay. Mean platelet PLA(2) activity was increased in individuals with Alzheimer's disease (p < 0.001). In VaD group the enzyme activity was between the values in AD and controls, these differences being significant from both groups. In the group of patients with ischemic stroke mean PLA(2) activity was higher either 48 h after the stroke or 7 days later (in both cases p < 0.001). The results may be particularly interesting in light of the fact, that inhibitors of PLA(2) activity are known.
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PMID:Platelet phospholipase A2 activity in patients with Alzheimer's disease, vascular dementia and ischemic stroke. 1744 2

Reactive oxygen species (ROS) are produced in mammalian cells through enzymic and non-enzymic mechanisms. Although some ROS production pathways are needed for specific physiological functions, excessive production is detrimental and is regarded as the basis of numerous neurodegenerative diseases. Among enzymes producing superoxide anions, NADPH oxidase is widespread in mammalian cells and is an important source of ROS in mediating physiological and pathological processes in the cardiovascular and the CNS. ROS production is linked to the alteration of intracellular calcium homeostasis, activation of Ca(2+)-dependent enzymes, alteration of cytoskeletal proteins, and degradation of membrane glycerophospholipids. There is evolving evidence that ROS produced by NADPH oxidase regulate neuronal functions and degrade membrane phospholipids through activation of phospholipases A(2) (PLA(2)). This review is intended to cover recent studies describing ROS generation from NADPH oxidase in the CNS and its downstream activation of PLA(2), namely, the group IV cytosolic cPLA(2) and the group II secretory sPLA(2). A major focus is to elaborate the dual role of NADPH oxidase and PLA(2) in mediating the oxidative and inflammatory responses in neurodegenerative diseases, including cerebral ischemia and Alzheimer's disease. Elucidation of the signaling pathways linking NADPH oxidase with the multiple forms of PLA(2) will be important in understanding the oxidative and degradative mechanisms that underline neuronal damage and glial activation and will facilitate development of therapeutic intervention for prevention and treatment of these and other neurodegenerative diseases.
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PMID:The roles of NADPH oxidase and phospholipases A2 in oxidative and inflammatory responses in neurodegenerative diseases. 1756 38

Several serine proteases including thrombin, tissue-type plasminogen activator and urokinase-type plasminogen activator have been well characterized in the brain. In this article, we review the brain-related trypsin and trypsin-like serine proteases. Accumulating evidence demonstrates that trypsin and trypsin-like serine proteases play very important roles in neural development, plasticity, neurodegeneration and neuroregeneration in the brain. Neuropsin is able to hydrolyze the extracellular matrix components by its active site serine, and regulates learning and memory in normal brain. The mutant neurotrypsin contributes to mental retardation in children. Neurosin seems to be involved in the pathogenesis of neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease or multiple sclerosis. Although mesotrypsin/trypsin IV is also implicated in neurodegeneration, its functional significance still remains largely unknown. Particularly, mesotrypsin/trypsin IV, P22 and neurosin exert their physiological and pathological functions through activation of certain protease-activated receptors (PARs). In the brain, the presence of serpins controls the activity of serine proteases. Therefore, understanding the interaction among brain trypsin, serpins and PARs will provide invaluable tools for regulating normal brain functions and for the clinical treatment of neural disorders.
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PMID:Trypsin and trypsin-like proteases in the brain: proteolysis and cellular functions. 1796 32

Phospholipase A(2) (PLA(2)), cyclooxygenase (COX) and prostaglandin (PG) synthase are enzymes involved in arachidonate cascade. PLA(2) liberates arachidonic acid (AA) from cell membrane lipids. COX oxidizes AA to PGG(2) followed by an endoperoxidase reaction that converts PGG(2) into PGH(2). PGs are generated from astrocytes, microglial cells and neurons in the central nervous system, and are altered in the brain of demented patients. Dementia is principally diagnosed into Alzheimer's disease (AD) and vascular dementia (VaD). In older patients, the brain lesions associated with each pathological process often occur together. Regional brain microvascular abnormalities appear before cognitive decline and neurodegeneration. The coexistence of AD and VaD pathology is often termed mixed dementia. AD and VaD brain lesions interact in important ways to decline cognition, suggesting common pathways of the two neurological diseases. Arachidonate cascade is one of the converged intracellular signal transductions between AD and VaD. PLA(2) from mammalian sources are classified as secreted (sPLA(2)), Ca(2+)-dependent, cytosolic (cPLA(2)) and Ca(2+)-independent cytosolic PLA(2) (iPLA(2)). PLA(2) activity can be regulated by calcium, by phosphorylation, and by agonists binding to G-protein-coupled receptors. cPLA(2) is upregulalted in AD, but iPLA(2) is downregulated. On the other hand, sPLA(2) is increased in animal models for VaD. COX-2 is induced and PGD(2) are elevated in both AD and VaD. This review presents evidences for central roles of PLA(2)s, COXs and PGs in the dementia.
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PMID:Cerebral arachidonate cascade in dementia: Alzheimer's disease and vascular dementia. 1861 38

Oligomeric amyloid-beta peptide (Abeta) is known to induce cytotoxic effects and to damage cell functions in Alzheimer's disease. However, mechanisms underlying the effects of Abeta on cell membranes have yet to be fully elucidated. In this study, Abeta 1-42 (Abeta(42)) was shown to cause a temporal biphasic change in membranes of astrocytic DITNC cells using fluorescence microscopy of Laurdan. Abeta(42) made astrocyte membranes became more molecularly-disordered within the first 30 min to 1 h, but gradually changed to more molecularly-ordered after 3 h. However, Abeta(42) caused artificial membranes of vesicles made of rat whole brain lipid extract to become more disordered only. The trend for more molecularly-ordered membranes in astrocytes induced by Abeta(42) was abrogated by either an NADPH oxidase inhibitor, apocynin, or an inhibitor of cytosolic phospholipase A(2) (cPLA(2)), but not by an inhibitor of calcium-independent PLA(2) (iPLA(2)). Apocynin also suppressed the increased production of superoxide anions (O(2)(-)) and phosphorylation of cPLA(2) induced by Abeta(42). In addition, hydrolyzed products of cPLA(2), arachidonic acid (AA), but not lysophosphatidylcholine (LPC) caused astrocyte membranes to become more molecularly-ordered. These results suggest (1) a direct interaction of Abeta(42) with cell membranes making them more molecularly-disordered, and (2) Abeta(42) also indirectly makes membranes become more molecularly-ordered by triggering the signaling pathway involving NADPH oxidase and cPLA(2) in astrocytes.
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PMID:Amyloid-beta peptide induces temporal membrane biphasic changes in astrocytes through cytosolic phospholipase A2. 1872 90

The importance of lipids in cell signaling and tissue physiology is demonstrated by the many CNS pathologies involving deregulated lipid metabolism. One such critical metabolic event is the activation of phospholipase A(2) (PLA(2)), which results in the hydrolysis of membrane phospholipids and the release of free fatty acids, including arachidonic acid, a precursor for essential cell-signaling eicosanoids. Reactive oxygen species (ROS, a product of arachidonic acid metabolism) react with cellular lipids to generate lipid peroxides, which are degraded to reactive aldehydes (oxidized phospholipid, 4-hydroxynonenal, and acrolein) that bind covalently to proteins, thereby altering their function and inducing cellular damage. Dissecting the contribution of PLA(2) to lipid peroxidation in CNS injury and disorders is a challenging proposition due to the multiple forms of PLA(2), the diverse sources of ROS, and the lack of specific PLA(2) inhibitors. In this review, we summarize the role of PLA(2) in CNS pathologies, including stroke, spinal cord injury, Alzheimer's, Parkinson's, Multiple sclerosis-Experimental autoimmune encephalomyelitis and Wallerian degeneration.
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PMID:Phospholipase A(2), reactive oxygen species, and lipid peroxidation in CNS pathologies. 1875 70

The serine protease tissue-type plasminogen activator (tPA), a key enzyme in hemostasis, is activated by protein aggregates with amyloid-like properties. tPA is implicated in various pathologies, including amyloidoses. A major task is to further elucidate the mechanisms of amyloid pathology. We here show that the fibronectin type I domain of tPA mediates the interaction with amyloid protein aggregates. We found that in contrast to full-length tPA, a deletion-mutant of tPA, lacking the first three N-terminal domains (including the fibronectin type I domain), fails to activate in response to amyloid protein aggregates. Using recombinantly produced domains of tPA in direct binding assays, we subsequently mapped the amyloid-binding region to the fibronectin type I domain. This domain co-localized with congophilic plaques in brain sections from patients with Alzheimer's disease. Fibronectin type I domains from homologous proteases factor XII, hepatocyte growth factor activator and from the extracellular matrix protein fibronectin also bound to aggregated amyloidogenic peptides. Finally, we demonstrated that the isolated fibronectin type I domain inhibits amyloid-induced aggregation of blood platelets. The identification of the fibronectin type I domain as an amyloid-binding module provides new insights into the (patho-) physiological role of tPA and the homologous proteins which may offer new targets for intervention in amyloid pathology.
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PMID:Identification of fibronectin type I domains as amyloid-binding modules on tissue-type plasminogen activator and three homologs. 1892 55

Neuronal expression of familial Alzheimer's disease-mutant human amyloid precursor protein (hAPP) and hAPP-derived amyloid-beta (Abeta) peptides causes synaptic dysfunction, inflammation and abnormal cerebrovascular tone in transgenic mice. Fatty acids may be involved in these processes, but their contribution to Alzheimer's disease pathogenesis is uncertain. We used a lipidomics approach to generate a broad profile of fatty acids in brain tissues of hAPP-expressing mice and found an increase in arachidonic acid and its metabolites, suggesting increased activity of the group IV isoform of phospholipase A(2) (GIVA-PLA(2)). The levels of activated GIVA-PLA(2) in the hippocampus were increased in individuals with Alzheimer's disease and in hAPP mice. Abeta caused a dose-dependent increase in GIVA-PLA(2) phosphorylation in neuronal cultures. Inhibition of GIVA-PLA(2) diminished Abeta-induced neurotoxicity. Genetic ablation or reduction of GIVA-PLA(2) protected hAPP mice against Abeta-dependent deficits in learning and memory, behavioral alterations and premature mortality. Inhibition of GIVA-PLA(2) may be beneficial in the treatment and prevention of Alzheimer's disease.
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PMID:Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease. 1893 64

In rats, phospholipase A(2) (PLA(2)) activity was found to be increased in the hippocampus immediately after training and retrieval of a contextual fear conditioning paradigm (step-down inhibitory avoidance [IA] task). In the present study we investigated whether PLA(2) is also activated in the cerebral cortex of rats in association with contextual fear learning and retrieval. We observed that IA training induces a rapid (immediately after training) and long-lasting (3 h after training) activation of PLA(2) in both frontal and parietal cortices. However, immediately after retrieval (measured 24 h after training), PLA(2) activity was increased just in the parietal cortex. These findings suggest that PLA(2) activity is differentially required in the frontal and parietal cortices for the mechanisms of contextual learning and retrieval. Because reduced brain PLA(2) activity has been reported in Alzheimer disease, our results suggest that stimulation of PLA(2) activity may offer new treatment strategies for this disease.
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PMID:Conditioning training and retrieval increase phospholipase A(2) activity in the cerebral cortex of rats. 1898 40

Kinetic methods in unanesthetized rodents have shown that turnover rates of arachidonic acid (AA) and docosahexaenoic acid (DHA) in brain membrane phospholipids are rapid and energy consuming and that phospholipase A(2) (PLA(2)) and acyl-CoA synthetase enzymes that regulate turnover are specific for one or the other PUFA. Thus, AA turnover in brain phospholipids was reduced, and AA-selective cytosolic cPLA(2) or acyl-CoA synthetase, as well as cyclooxygenase (COX)-2, were downregulated in brains of rats given drugs effective against bipolar disorder, whereas DHA turnover and expression of DHA-selective calcium-independent iPLA(2) were unchanged. Additionally, the brain AA and DHA cascades can be altered reciprocally by dietary or genetic conditions. Thus, following 15 wk of dietary (n-3) PUFA deprivation, DHA loss from rat brain was slowed because of reduced iPLA(2) and COX-1 expression, whereas AA-selective cPLA(2), sPLA(2), and COX-2 were upregulated, as were AA and docosapentaenoic acid concentrations. Measured rates of AA and DHA incorporation into brain represent their respective rates of metabolic consumption, because these PUFA are not synthesized de novo or converted significantly from their precursors in brain. In healthy human volunteers, positron emission tomography (PET) was used to show that the brain consumes AA and DHA at respective rates of 17.8 and 4.6 mg/d, whereas in patients with Alzheimer disease, AA consumption is elevated. In the future, PET could be used to relate human brain rates of AA and DHA consumption to liver PUFA metabolism and dietary PUFA intake.
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PMID:Arachidonic acid and the brain. 1902 81


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