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)

We performed a cross-sectional case-control study among 277 subjects with dementia and 298 control subjects drawn from participants of the Rotterdam Study, a population-based cohort study among subjects aged 55 years or over, and from participants of the Rotterdam Stroke Databank, a hospital-based stroke registry, with the objective to evaluate the association of indicators of coagulability, fibrinogen, prothrombin fragments 1+2, thrombin-antithrombin complex (TAT), and indicators of fibrinolysis, plasmin-inhibitor complex, D-dimer and tissue-type plasminogen activator (t-PA) with dementia. Increased levels of TAT, D-dimer and t-PA activity were associated with an increased risk of dementia. Additional stratified analyses indicated that an increased TAT level was the primary factor related to dementia. The present study provides evidence that predominantly increased thrombin generation is associated with dementia.
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PMID:Coagulation and fibrinolysis markers and risk of dementia. The Dutch Vascular Factors in Dementia Study. 1042 69

Allostasis designates processes of bodily adaptation to stressful challenges, whereas allostatic load means the costs of wear and tear to the body as a consequence of inefficient allostasis. In distressed dementia caregivers, an acute procoagulant stress response might be one dynamic mediator of allostatic load relevant to cardiovascular endpoints. An interviewer assessed the number of negative life-events independent from caregiving over 4 weeks in 37 spousal Alzheimer caregivers (M age +/- SD = 72 +/- 6 years). Baseline procoagulability scores and procoagulability scores in response to a 15-min speech task included plasma thrombin/antithrombin III complex, D-dimer, von Willebrand factor, tissue-type plasminogen activator, and plasminogen activator inhibitor 1 levels. Allostatic load was defined as the difference in procoagulability scores from baseline to speech, using standardized (z-score) transformations. Speech stress significantly increased heart rate (p =.017), systolic blood pressure (p =.002), and diastolic blood pressure (p <.001). The number of negative life-events (M +/- SD 2.8 +/- 2.0) correlated with allostatic load (r =.367, p =.026). After controlling for age and smoking, which together explained 32% of the variance in the allostatic load (R2 =.324), F(2, 34) = 8.14, p =.001, the number of negative life-events accounted for an additional 13% of that variance (Delta R2=.125), Delta F(1, 33) = 7.49, p =.010. The finding is compatible with the concept of allostasis and allostatic load, suggesting that higher combined caregiving and life distress levels are associated with more dysfunctional hemostatic responses to acute mental stress. The acute procoagulant stress response might constitute a dynamic mediator of allostatic load in Alzheimer caregivers.
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PMID:Acute procoagulant stress response as a dynamic measure of allostatic load in Alzheimer caregivers. 1286 53

Neuroserpin is a member of the serine proteinase inhibitor (serpin) gene family that reacts preferentially with tissue-type plasminogen activator (tPA) and is primarily localized to neurons in regions of the brain where tPA is also found. Outside of the central nervous system (CNS) tPA is predominantly found in the blood where its primary function is as a thrombolytic enzyme. However, tPA is also expressed within the CNS where it has a very different function, promoting events associated not only with synaptic plasticity but also with cell death in a number of settings, such as cerebral ischemia and seizures. Neuroserpin is released from neurons in response to neuronal depolarization and plays an important role in the development of synaptic plasticity. Following the onset of cerebral ischemia there is an increase in both tPA activity and neuroserpin expression in the area surrounding the necrotic core (ischemic penumbra), and treatment with neuroserpin following ischemic stroke or overexpression of the neuroserpin gene results in a significant decrease in the volume of the ischemic area as well as in the number of apoptotic cells. TPA activity and neuroserpin expression are also increased in specific areas of the brain by seizures, and treatment with neuroserpin slows the progression of seizure activity throughout the CNS and results in significant neuronal survival in the hippocampus. Mutations in human neuroserpin result in a form of autosomal dominant inherited dementia which is characterized by the presence of intraneuronal inclusion bodies and is known as Familial Encephalopathy with Neuroserpin Inclusion Bodies.
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PMID:Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system. 1498 20

Regional hypoperfusion, associated with a reduction in cerebral metabolism, is a hallmark of Alzheimer's disease (AD) and contributes to cognitive decline. Cerebral perfusion and hence cognition can be enhanced by exercise. The present review describes first how the effects of exercise on cerebral perfusion in AD are mediated by nitric oxide (NO) and tissue-type plasminogen activator, the release of which is regulated by NO. A conclusion of clinical relevance is that exercise may not be beneficial for the cognitive functioning of all people with dementia if cardiovascular risk factors are present. The extent to which cardiovascular risk factors play a role in the selection of older people with dementia in clinical studies will be addressed in the second part of the review in which the effects of exercise on cognition are presented. Only eight relevant studies were found in the literature, emphasizing the paucity of studies in this field. Positive effects of exercise on cognition were reported in seven studies, including two that excluded and two that included patients with cardiovascular risk factors. These findings suggest that cardiovascular risk factors do not necessarily undo the beneficial effects of exercise on cognition in cognitively impaired people. Further research is called for, in view of the limitations of the clinical studies reviewed here.
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PMID:Exercise, cognition and Alzheimer's disease: more is not necessarily better. 1635 29

Proteinases and their inhibitors play important roles in neural development, homeostasis and disease. Neuroserpin is a member of the serine proteinase inhibitor (serpin) superfamily that is secreted from the growth cones of neurons and inhibits the enzyme tissue-type plasminogen activator (tPA). The temporal and spatial pattern of neuroserpin expression suggests a role in synaptogenesis and is most prominent in areas of the brain that participate in learning, memory and behaviour. Neuroserpin also provides neuronal protection in pathologies such as cerebral ischaemia and epilepsy by preventing excessive activity of tPA. Point mutations in neuroserpin cause aberrant conformational transitions and the formation of loop-sheet polymers that are retained within the endoplasmic reticulum of neurons, forming inclusion bodies that underlie an autosomal dominant dementia that we have called familial encephalopathy with neuroserpin inclusion bodies or FENIB. We review here the role of neuroserpin and other proteinase inhibitors in brain development, function and disease.
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PMID:Neuroserpin: a serpin to think about. 1646 51

Mild cognitive impairment (MCI) is generally referred to the transitional zone between normal cognitive function and early dementia or clinically probable Alzheimer's disease (AD). Oxidative stress plays a significant role in AD and is increased in the superior/middle temporal gyri of MCI subjects. Because AD involves hippocampal-resident memory dysfunction, we determined protein oxidation and identified the oxidized proteins in the hippocampi of MCI subjects. We found that protein oxidation is significantly increased in the hippocampi of MCI subjects when compared to age- and sex-matched controls. By using redox proteomics, we determined the oxidatively modified proteins in MCI hippocampus to be alpha-enolase (ENO1), glutamine synthetase (GLUL), pyruvate kinase M2 (PKM2) and peptidyl-prolyl cis/trans isomerase 1 (PIN1). The interacteome of these proteins revealed that these proteins functionally interact with SRC, hypoxia-inducible factor 1, plasminogen (PLG), MYC, tissue plasminogen activator (PLAT) and BCL2L1. Moreover, the interacteome indicates the functional involvement of energy metabolism, synaptic plasticity and mitogenesis/proliferation. Therefore, oxidative inactivation of ENO1, GLUL and PIN1 may alter these cellular processes and lead to the development of AD from MCI. We conclude that protein oxidation plays a significant role in the development of AD from MCI and that the oxidative inactivation of ENO1, GLUL, PKM2 and PIN1 is involved in the progression of AD from MCI. The current study provides a framework for future studies on the development of AD from MCI relevant to oxidative stress.
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PMID:Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer's disease. 1646 29

Phospholipase A(2) (PLA(2)) is a key enzyme in cerebral phospholipid metabolism. Preliminary post-mortem studies have shown that PLA(2) activity is decreased in frontal and parietal areas of the AD brain, which is in accordance with recent (31)P-Magnetic Resonance Spectroscopy evidence of reduced phospholipid turnover in the pre-frontal cortex of moderately demented AD patients. Such abnormality may also be observed in peripheral cells, and reduced PLA(2) activity in platelet membranes of AD patients, and correlates with the severity of dementia. In rat hippocampal slices, PLA(2) has been implicated in mechanisms of synaptic plasticity. In adult rats, the stereotaxic injection of PLA(2) inhibitors in the CA1 area of hippocampus impaired, in a dose-dependent manner, the formation of short- and long-term memory. Additionally, such inhibition resulted in a reduction of the fluidity of hippocampal membranes. In primary cultures of cortical and hippocampal neurons, the inhibition of PLA(2) precluded neurite outgrowth, and the sustained inhibition of the enzyme in mature cultures lead to loss of viability. Taken together, these findings reinforce the involvement of PLA(2) enzymes in neurodevelopment and neurodegeneration processes, and further suggest that reduced PLA(2) activity, probably reducing membrane phospholipids breakdown, may contribute to the memory impairment in AD.
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PMID:The role of phospholipase A2 in neuronal homeostasis and memory formation: implications for the pathogenesis of Alzheimer's disease. 1713 Dec 32

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

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

Neuroserpin is a selective inhibitor of tissue-type plasminogen activator (tPA) that plays an important role in neuronal plasticity, memory, and learning. We report here the crystal structure of native human neuroserpin at 2.1 A resolution. The structure has a helical reactive center loop and an omega loop between strands 1B and 2B. The omega loop contributes to the inhibition of tPA, as deletion of this motif reduced the association rate constant with tPA by threefold but had no effect on the kinetics of interaction with urokinase. Point mutations in neuroserpin cause the formation of ordered intracellular polymers that underlie dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB). Wild-type neuroserpin is also unstable and readily forms polymers under near-physiological conditions in vitro. This is, in part, due to the substitution of a conserved alanine for serine at position 340. The replacement of Ser340 by Ala increased the melting temperature by 3 degrees C and reduced polymerization as compared to wild-type neuroserpin. Similarly, neuroserpin has Asn-Leu-Val at the end of helix F and thus differs markedly from the Gly-X-Ile consensus sequence of the serpins. Restoration of these amino acids to the consensus sequence increased thermal stability and reduced the polymerization of neuroserpin and its transition to the latent conformer. Moreover, introduction of the consensus sequence into S49P neuroserpin that causes FENIB increased the stability and inhibitory activity of the mutant, as well as blocked polymerization and increased the yield of protein during refolding. These data provide a molecular explanation for the inherent instability of neuroserpin and the effect of point mutations that underlie the dementia FENIB.
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PMID:The 2.1-A crystal structure of native neuroserpin reveals unique structural elements that contribute to conformational instability. 1928 87


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