Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alzheimer's disease (AD) and dementia with vascular component (DVC) are the most prevalent forms of dementia. Both clinical entities share many similarities, but they differ in major phenotypic and genotypic profiles as revealed by structural and functional genomics studies. Comparative phenotypic studies have identified significant differences in 25% of more than 100 parametric variables, including anthropometry, cardiovascular function, aortic atherosclerosis, brain atrophy, blood pressure, blood biochemistry, hematology, thyroid function, folate and vitamin B12 levels, brain hemodynamics and lymphocyte markers. The phenotypic profile of patients with DVC differs from that of AD patients in the following: anthropometric values (weight, height); cardiovascular function (ECG, heart rate); blood pressure; lipid metabolism (HDL-CHO, TGs); uric acid metabolism; peripheral calcium homeostasis; liver function (GOT, GPT, GGT); alkaline phosphatase; lactate dehydrogenase; red and white blood cells; regional brain atrophy (left temporal region, inter-hippocampal distance); and left anterior blood flow velocity. Functional genomics studies incorporating APOE-related changes in biological markers extended the difference between AD and DVC up to 57%. Brain perfusion studies show a severe brain hypoperfusion in dementia associated with enlarged age-dependent arterial perfusion times. Structural genomics studies with AD-related genes, including APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, cFOS and PRNP genes, demonstrate different genetic profiles in AD and DVC, with an absolute genetic variation rate ranging from 30% to 80%, depending upon genes and genetic clusters. Single gene analysis identifies relative genetic variations ranging from 0% to 5%. The relative polymorphic variation in genetic clusters integrated by two, three or four genes associated with AD ranges from 1% to 3%. The main phenotypic differences between AD and DVC are genotype-dependent, especially in AD, probably indicating that different genomic factors are determinant for the expression of dementia symptoms which might be accelerated or induced by environmental and/or cerebrovascular factors.
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PMID:Phenotypic profiles and functional genomics in Alzheimer's disease and in dementia with a vascular component. 1526 64

Constitutive genomics are probably determinant for the onset of dementia in conjunction with cerebrovascular and environmental factors. Furthermore, pharmacogenomic studies predict that the therapeutic response in Alzheimer's disease (AD) is genotype-specific, and that the expression of genes involved in the regulation of drug metabolism can influence efficacy and safety issues in pharmacotherapy. AD and dementia with a vascular component (DVC = VD + MXD) are the most prevalent forms of dementia. These clinical entities share many similarities, but they differ in major phenotypic and genotypic profiles, as revealed by structural and functional genomics studies. Comparative phenotypic studies have identified significant differences in 25% of more than 100 parametric variables, including anthropometry, cardiovascular function, aortic atherosclerosis, brain atrophy, blood pressure, blood biochemistry, hematology, thyroid function, folic acid and vitamin B(12) levels, brain hemodynamics and lymphocyte markers. The phenotypic profile of patients with DVC differs from that of AD patients in the following: (a) anthropometric values, (b) cardiovascular function, (c) blood pressure, (d) lipid metabolism, (e) uric acid levels, (f) peripheral calcium levels, (g) liver function (GOT, GPT, GGT), (h) alkaline phosphatase, (i) lactate dehydrogenase, (j) red and white blood cells, (k) regional brain atrophy (left temporal region, inter-hippocampal distance) and (l) brain blood flow velocity. Functional genomics studies incorporating APOE-related changes in biological markers extended the difference between AD and DVC up to 57%. Structural genomics studies with AD-related genes, including APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, cFOS and PRNP genes, demonstrate different genetic profiles in AD and DVC, with an absolute genetic variation rate ranging from 30 to 80%, depending upon genes and genetic clusters. Single gene analysis identifies relative genetic variations ranging from 0 to 5%. The relative polymorphic variation in genetic clusters integrated by 2, 3 or 4 genes associated with AD ranges from 1 to 3%. The main phenotypic differences between AD and DVC are genotype-dependent, especially in AD, probably indicating that different genomic factors are essential for the expression of dementia symptoms that might be accelerated or induced by environmental and/or cerebrovascular factors.
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PMID:Genomics and phenotypic profiles in dementia: implications for pharmacological treatment. 1534 38

The microtubule-associated protein tau aggregates intracellularly by unknown mechanisms in Alzheimer's disease and other tauopathies. A contributing factor may be a failure to break down free cytosolic tau, thus creating a surplus for aggregation, although the proteases that degrade tau in brain remain unknown. To address this issue, we prepared cytosolic fractions from five normal human brains and from perfused rat brains and incubated them with or without protease inhibitors. D-Phenylalanyl-L-prolylarginyl chloromethyl ketone, a thrombin-specific inhibitor, prevented tau breakdown in these fractions, suggesting that thrombin is a brain protease that processes tau. We next exposed human recombinant tau to purified human thrombin and analyzed the fragments by N-terminal sequencing. We found that thrombin proteolyzed tau at multiple arginine and lysine sites. These include Arg(155)-Gly(156), Arg(209)-Ser(210), Arg(230)-Thr(231), Lys(257)-Ser(258), and Lys(340)-Ser(341) (numbering according to the longest human tau isoform). Temporally, the initial cleavage occurred at the Arg(155)-Gly(156) bond. Proteolysis of the resultant C-terminal tau fragment then proceeded bidirectionally. When tau was phosphorylated by glycogen synthase kinase-3beta, most of these proteolytic processes were inhibited, except for the first cleavage at the Arg(155)-Gly(156) bond. Furthermore, paired helical filament tau prepared from Alzheimer's disease brain was more resistant to thrombin proteolysis than following dephosphorylation by alkaline phosphatase. The results suggest a possible role for thrombin in proteolysis of tau under physiological and/or pathological conditions in human brains. They are consistent with the hypothesis that phosphorylation of tau inhibits proteolysis by thrombin or other endogenous proteases, leading to aggregation of tau into insoluble fibrils.
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PMID:Proteolysis of non-phosphorylated and phosphorylated tau by thrombin. 1554 98

More than 180 genes distributed across the human genome are potentially involved in the pathogenesis of Alzheimer's disease (AD). The AD population shows a higher genetic variation rate than the control population. Significant differences in allelic distribution and frequency exist when AD-related polygenic clusters are compared with other forms of dementia, indicating that the genetic component in neurodegenerative dementia differs from that of other CNS disorders. The characterization of AD genotype-related phenotypic profiles reveals substantial differences in biological markers among AD clusters associated with different genes and/or allelic combinations. AD and dementia with vascular component (DVC) are the most prevalent forms of dementia. Both clinical entities share many similarities, but they differ in their major phenotypic and genotypic profiles, as revealed by structural and functional genomics studies. Comparative phenotypic studies have identified significant differences in 25% of more than 100 parametric variables, including anthropometric values, cardiovascular function, blood pressure, lipid metabolism, uric acid metabolism, peripheral calcium homeostasis, liver function, alkaline phosphatase, lactate dehydrogenase, red and white blood cells, regional brain atrophy, and brain blood flow velocity. Functional genomic studies incorporating apolipoprotein E (APOE)-related changes in biological markers extended the difference between AD and DVC by up to 57%. Structural genomic studies with AD-related genes, including APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, cFOS, and PRNP, demonstrate different genetic profiles in AD and DVC, with an absolute genetic variation rate in the range of 30-80%, depending upon genes and genetic clusters. The relative polymorphic variation in genetic clusters integrated by two, three or four genes associated with AD ranges from 1 to 3%. The main phenotypic differences in AD are genotype dependent, indicating a powerful influence of polygenic factors on the AD phenotypic profile. All these genotypic and phenotypic variations bring about important consequences for the pharmacogenomics of AD.
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PMID:Genomic characterization of Alzheimer's disease and genotype-related phenotypic analysis of biological markers in dementia. 1558 76

Apolipoprotein E (apoE) 4 and aging are risk factors for Alzheimer's disease (AD). Mice expressing human apoE4 and aged wild-type mice show a similarity in the transbilayer distribution of cholesterol in synaptic plasma membranes (SPMs) but differ markedly compared with apoE3 mice and young mice. The largest changes in cholesterol distribution were observed in the SPM exofacial leaflet where there was a doubling of cholesterol. Lipid rafts are thought to be associated with the exofacial leaflet, and we proposed that lipid raft protein and lipid composition would be associated with apoE genotype and age. Lipid rafts were isolated from synaptosomes of different age groups (2, 12, 24 months) of mice expressing human apoE3 and apoE4. Lipid raft markers, alkaline phosphatase (ALP), flotillin-1, cholesterol and sphingomyelin (SM) were examined. Lipid rafts of young apoE4 mice were more similar to older mice as compared with young apoE3 mice in reductions in alkaline phosphatase activity and flotillin-1 abundance. Lipid raft cholesterol and sphingomyelin levels were not significantly different between the young apoE3 and apoE4 mice but cholesterol levels of lipid rafts did increase with age in both genotypes. Results of the present study demonstrate that the two risk factors for Alzheimer's disease, apoE4 genotype and increasing age have similar effects on brain lipid raft protein markers and these findings support the notion that the transbilayer distribution of cholesterol is associated with lipid raft function.
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PMID:Murine synaptosomal lipid raft protein and lipid composition are altered by expression of human apoE 3 and 4 and by increasing age. 1576 Jun 44

Recently, we developed a novel fluorescent method named intrinsic fluorescence induction that allows direct visualization of neurofibrillary pathology without introducing exogenous chromogens. In the present study, we further characterized the properties of this novel red fluorescence biophysically, biochemically, and neuropathologically. In vitro spectrofluorometry and in situ emission scan show that the intrinsic fluorescence of neurofibrillary tangles has a long emission wavelength peak at 620 nm and a large Stoke's shift of 70 nm. Dephosphorylation of Alzheimer's disease brain sections with alkaline phosphatase or denaturation with guanidine only causes a subtle reduction in the induced fluorescence of neurofibrillary tangles, while hydrofluoric acid or formic acid completely eliminates the fluorescence. Chemical modification of residue serine, but not tyrosine or tryptophan, reduced the intensity of induced fluorescence significantly. The induced fluorophore, thus, has unique properties, and its generation likely depends on the particular conformation of paired helical filaments, which may in turn depend on tau hyperphosphorylation.
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PMID:Biophysical and biochemical characterization of the intrinsic fluorescence from neurofibrillary tangles. 1594 72

Noninvasive real-time quantification of cellular protease activity allows monitoring of enzymatic activity and identification of activity modulators within the protease's natural milieu. We developed a protease activity assay based on differential localization of a recombinant reporter consisting of a Golgi retention signal and a protease cleavage sequence fused to alkaline phosphatase (AP). When expressed in mammalian cells, this protein localizes to Golgi bodies and, on protease-mediated cleavage, AP translocates to the extracellular medium where its activity is measured. We used this system to monitor the Golgi-associated protease furin, a pluripotent enzyme with a key role in tumorigenesis, viral propagation of avian influenza, ebola, and HIV as well as in activation of anthrax, pseudomonas, and diphtheria toxins. This technology was adapted for high-throughput screening of 39,000-compound small molecule libraries, leading to identification of furin inhibitors. Furthermore, this strategy was used to identify inhibitors of another Golgi protease, the beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE). BACE cleavage of the APP leads to formation of the Abeta peptide, a key event that leads to Alzheimer's disease. In conclusion, we describe a customizable noninvasive technology for real-time assessment of Golgi protease activity used to identify inhibitors of furin and BACE.
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PMID:Identification of inhibitors using a cell-based assay for monitoring Golgi-resident protease activity. 1731 41

We investigated capillary density in 12 subjects with leukoaraiosis (LA), in 9 age-matched normal subjects, in 7 cases of Alzheimer's disease (AD), and 4 after whole-brain irradiation for brain tumors. In the LA study (which as been published), autopsy brains were evaluated by MRI. The presence of LA was indicated by confluent or patchy areas of hyperintensity in the deep white matter. We employed a stereology method using computerized image processing and analysis to determine microvascular density. Afferent vessels (arterioles and capillaries, but not veins or venules) were stained for alkaline phosphatase in 100 microm thick celloidin sections. Microvascular density in LA lesions in the deep white matter (2.56%) was significantly lower than in the corresponding deep white matter of normal subjects (3.20%, p=0.0180). LA subjects demonstrated decreased vascular density at early ages (55-65 years) when compared to normal subjects. Our findings indicate that LA affects the brain globally, with capillary loss, although the parenchymal damage is found primarily in the deep white matter. In ongoing studies of the deep white matter in AD brains, we found a pattern of decreased vascular density compared to normal, as well as an age-related decline. In the four irradiated brains, we found very low vessel densities, similar to those found in LA, without an additional age-related decline.
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PMID:Vascular dementia in leukoaraiosis may be a consequence of capillary loss not only in the lesions, but in normal-appearing white matter and cortex as well. 1732 Sep 9

Arteriolar tortuousities, consisting of vascular coils, loops, and spirals, appear in white matter in a subset of human cerebral vessels. Computerized morphometry was used to analyze brain sections from a broad age range of subjects to determine whether tortuosity is a phenomenon of aging or is associated with leukoaraiosis (LA) or Alzheimer disease (AD). Autopsy brains were studied from 55 subjects ranging in age from 23 weeks postconception to 102 years. Fourteen aged subjects were diagnosed with LA and 7 with AD. By using computerized morphometry, vascular curl (curvilinear length/straight length) was measured in white matter arterioles in 100-microm-thick, alkaline phosphatase-stained sections. Aging subjects, compared with young subjects, showed significant increases in both the prevalence and severity of tortuosity. Curl scores in aged subjects with LA or AD were not significantly different from aged controls without LA or AD. We conclude that 1) tortuous vessels are extremely rare in preterm babies, children, or young adults; 2) significant tortuosity, as indicated by elevated curl scores, begins in middle age; 3) tortuosity does not appear in a subset of aged individuals regardless of longevity; and 4) tortuosity does not appear in a subset of individuals with either LA or AD.
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PMID:Morphometric analysis of arteriolar tortuosity in human cerebral white matter of preterm, young, and aged subjects. 1748 90

Oxidative damage to proteins, implicated amongst other in the etiology and progression of Parkinson's disease (PD) and Alzheimer's disease (AD), results in the loss of specific biological protein function. A simple, sensitive, and cost-effective fluorimetric test to assess the antioxidant capacity of new chemical entities to protect proteins from loss of activity caused by reactive oxygen species (ROS) was developed using alkaline phosphatase (ALP) as model protein. Protein oxidation was induced by 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH) and the decrease in catalytic activity of ALP to hydrolyze 4-methylumbelliferyl phosphate (4-MUP) to fluorescent 4-methylumbelliferone (4-MU) was monitored as a marker of protein degradation. According to their capacity to protect ALP from peroxyl radical-induced activity loss, ten reference antioxidants were divided into three classes, namely efficient (pIC(50) > 5 for quercetin, chlorogenic acid, caffeic acid, mangiferin, and resveratrol), intermediate (4 < pIC(50) < or = 5 for melatonin, trolox, and ascorbic acid), and poor antioxidants (pIC(50) < 4 for glutathione and D-mannitol). Multifunctional drugs, having the ability to interact with several disease-related targets are of interest in PD. Therefore, the capacity of three catechol-O-methyltransferase (COMT) inhibitors, entacapone, nitecapone, and tolcapone to protect ALP from oxidative damage was also investigated and found to be very similar to the most potent reference antioxidants.
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PMID:Novel screening assay for antioxidant protection against peroxyl radical-induced loss of protein function. 1770 59


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