Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The origin of beta-amyloid deposited in senile plaques in Alzheimer's disease (AD) is not known. We compared the expression of protein precursor of beta-amyloid (APP) in the cell types involved in plaque formation. The levels of APP mRNA were determined in primary rat neurons and glial cells in culture, human endothelial cells and in a murine brain-derived endothelial cell line. Northern blot analysis was performed using an APP cDNA probe to detect the general APP sequence and an oligonucleotide (40 mer) complementary to the sequence of the Kunitz protease inhibitor (APP-KPI). The APP mRNA transcripts were abundant in all three cell types. The highest level of APP, normalized to beta-actin mRNA content, was expressed in neurons, followed by glial cells, where the APP expression was similar (94%) while in endothelial cells was lower (53%). The proportion between APP-KPI mRNA and total APP mRNA was high in endothelial, intermediate in glial and low in neuronal cells. We compared the effects of exposure to interleukin-1 (IL-1), a cytokine involved in several biological processes and elevated in AD, on APP mRNA expression in neuronal, glial and endothelial cells. In human endothelial and in brain-derived murine endothelial cells we observed a similar increase (50%) of total APP mRNA or APP-KPI mRNA after treatment with human recombinant IL-1 beta. In neuronal cells, IL-1 (200 ng/ml) substantially increased APP mRNA (175%), detected with both probes. In glial cells, the expression of APP mRNA did not appear to be altered by IL-1 (50-400 ng/ml). The results suggest a role of IL-1 in the neuronal mechanisms related to beta-amyloid protein deposition in AD.
Brain Res Mol Brain Res 1992 Nov
PMID:Expression of amyloid precursor protein mRNAs in endothelial, neuronal and glial cells: modulation by interleukin-1. 133 90

An S1 nuclease protection assay was designed to study the splicing pattern of the alternatively spliced beta A4 amyloid gene (APP gene) of Alzheimer's disease (AD). We determined the splicing pattern of the APP gene in fetal, adult, aged adult and AD human cortex. The results suggest that alternative splicing of the APP gene in AD is not significantly different from age-matched controls, but distinct from the developing fetal brain.
Brain Res Mol Brain Res 1991 Feb
PMID:Alternative splicing of the beta A4 amyloid gene of Alzheimer's disease in cortex of control and Alzheimer's disease patients. 185 28

The ultrastructural and biochemical changes produced by 4-aminopyrazolo[3,4-d]pyrimidine (4-APP), on zona fasciculata cells of rat adrenal cortex are described. Male rats weighing approximately 200 g were injected intraperitoneally with 50 mg/kg/day of 4-APP for 3 days; the controls were injected with buffer. All animals were sacrificed on the 4th day and the adrenals from some of them were processed for electron microscopy. The adrenals from the remaining rats were used for measurements of gland cholesterol and corticosterone; the latter was also measured in the blood. In 4-APP-treated rats the zona fasciculata cells exhibited an increase in the amount of smooth endoplasmic reticulum and in the number of free ribosomes, often arranged in polyribosomes, and a decrease in the number of lipid droplets. The nucleus showed scarce condensed chromatin and nucleolar fragmentation. The quantitative analysis showed a significant increase of the volumetric density of endoplasmic reticulum and a significant decrease of the lipid droplets in treated rats when compared with controls. Concerning the nucleus, the volumetric density of condensed chromatin significantly decreased, while the relative volume of fibrillar centers, and of granular and vacuolar components increased. In treated rats, the adrenal cholesterol and corticosterone concentrations and the blood corticosterone level were significantly decreased. These data show that 4-APP has a remarkable effect on corticosteroidogenesis and depletes the pool of adrenal cholesteryl esters, and these data stress the importance of plasma cholesterol in the steroidogenesis; on the other hand the drug appears to have a direct effect on the nucleus.
J Ultrastruct Mol Struct Res
PMID:Ultrastructural and biochemical alterations produced in rat adrenal cortex by 4-aminopyrazolopyrimidine. 345 62

Most freshly isolated Trypanosoma cruzi blood trypomastigotes were insensitive to allopurinol (HPP) and 4-aminopyrazolo(3,4-d)pyrimidine (APP). Strains EP and Ya were, however, strongly inhibited by both drugs while strains DS and A-35 were HPP-insensitive but APP-sensitive. In contrast, epimastigotes resulting from one in vitro passage of all eleven T. cruzi strains were highly sensitive to both drugs. While hypoxanthine/guanine and adenine phosphoribosyltransferase and succino-AMP synthetase activities were similar in trypomastigotes of sensitive and insensitive T. cruzi strains, the uptake and metabolism of [14C]HPP and [14C]APP was significantly slower in T. cruzi trypomastigotes of insensitive strains than in sensitive strains. The results suggest the importance of drug uptake rates in determining the pyrazolopyrimidine sensitivity of different T. cruzi strains.
Mol Biochem Parasitol 1984 Apr
PMID:Differences in allopurinol and 4-aminopyrazolo(3,4-d) pyrimidine metabolism in drug-sensitive and insensitive strains of Trypanosoma cruzi. 637 52

The expression of L-beta A4 amyloid precursor protein (L-APP) mRNA, which is a splicing product excluding exon 15 of the APP gene, was investigated in various tissues of adult rats by a polymerase chain reaction analysis of reverse-transcribed RNA (RT-PCR). L-APP mRNA was ubiquitously expressed in all the examined tissues including the liver, kidney, heart, skeletal muscle, spleen, thymus, adrenal, stomach, submandibular gland, testis and ovary, except for the central nervous system (CNS) tissues such as the brain and spinal cord. The DNA sequence analysis of the RT-PCR products from adult rat liver showed an L-APP cDNA form, in which exon 14 was spliced from exon 14 to exon 16, and exon 15 of the APP gene was excluded. In addition, regarding as the brain and liver, L-APP mRNA expression was examined during the development of the embryonic stage. In the brain, no L-APP mRNA expression was detected even in the embryonic stage, whereas L-APP mRNA expression of the liver was still found in the embryonic stage. These results suggest that the splicing event excluding exon 15, which is exactly adjacent to exon 16 and exon 17 encoding the beta A4 protein, would probably occur very rarely in the CNS and that the splicing of L-APP might already be regulated in the embryonic stage.
Brain Res Mol Brain Res 1993 Nov
PMID:Alzheimer's amyloid precursor protein mRNA without exon 15 is ubiquitously expressed except in the rat central nervous system. 750 74

APP695 mRNA is only expressed in the brains of SAM. The expression of APP mRNA in SAM P1 mice brains is more marked than that in SAM R1 mice brain. APP mRNA expression was increased with advancing age in all brain regions of SAM P1 mice compared with SAM R1. Especially, the changes of the amount of APP mRNA in the prosencephalon and the mesencephalon are significant at P value of 0.05. We suggest that overexpression of APP mRNA may be related to accelerated aging phenomenon in the SAM brain. This is the first report of age-related increase in the amount of APP mRNA in the SAM brain.
Comp Biochem Physiol B Biochem Mol Biol 1995 Oct
PMID:Age-related changes of mRNA expression of amyloid precursor protein in the brain of senescence-accelerated mouse. 758 67

The aminopyrimidopyrimidine nucleoside 4-amino-8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine (APP), which was previously shown to possess experimental antitumor and antiviral activity, was metabolized within WI-L2 human lymphoblastoid cells to a derivative identified as the beta-D-ribonucleotide (APP-MP). In a subline of WI-L2 cells deficient in adenosine kinase, this metabolite was not formed and APP was not cytotoxic, suggesting that APP is converted by adenosine kinase to its 5'-monophosphate. Because no evidence of di- or triphosphates was seen, the monophosphate appeared to be the active species. Treatment of WI-L2 or L1210 cells with APP (10 microM) for 30 min caused extensive depletion of both purine and pyrimidine ribonucleotides. Purine and pyrimidine deoxyribonucleotides were also depleted. Cells were not protected from the cytotoxicity of APP by hypoxanthine plus uridine, but uridine plus adenosine plus 2-deoxycoformycin gave considerable protection. This result was consistent with APP-MP acting as an inhibitor of 5-phosphoribosyl-1-pyrophosphate (PRPP) synthetase, a hypothesis that was confirmed by preparing PRPP synthetase from Novikoff hepatoma cells; APP-MP was a noncompetitive inhibitor, with a Ki of 0.43 mM. APP-MP was found to accumulate in APP-treated cells to a concentration of almost 3 mM. The relevance of PRPP synthetase inhibition to the cytotoxic mechanism of APP is indicated by the fact that depletion of the PRPP pool was seen as early as 15 min after treatment, before any change was apparent in cellular levels of ATP or UTP. DNA synthesis was markedly suppressed within 30 min of APP treatment of WI-L2 cells, and a lesser degree of inhibition of RNA synthesis was apparent after 45 min.
Mol Pharmacol 1993 Aug
PMID:Inhibition of 5-phosphoribosyl-1-pyrophosphate synthetase by the monophosphate metabolite of 4-amino-8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine: a novel mechanism for antitumor activity. 768 45

The kinetics of inhibition by the aminopyrimidopyrimidine nucleotide 4-amino-8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine[-5' -monophosphate (APP-MP) were assessed with two human isozymes of 5-phosphoribosyl-1-pyrophosphate synthetase (PRS) (PRS1 and PRS2) and a mutant enzyme, S.M. PRS1, derived from an individual with PRS hyperactivity. In the presence of 1 mM potassium phosphate, APP-MP inhibited PRS1 and PRS2 with half-maximal inhibition (IC50) at 5.2 microM and 23.8 microM, respectively. The degree of inhibition for both enzymes was highly dependent on the phosphate concentration; IC50 values were 70 times higher in the presence of 50 mM potassium phosphate. APP-MP exhibited mixed noncompetitive-uncompetitive inhibition against PRS1, with a Kii value of 6.1 microM and a Kis value of 14.6 microM, and produced parabolic secondary plots of slope or intercept versus APP-MP concentration. In comparison, inhibition of PRS1 by ADP was of a mixed noncompetitive-competitive type, with a Kii value of 9.6 microM and a Kis value of 2.8 microM. A similar kinetic analysis was completed using S.M. PRS1, a mutant enzyme with a single amino acid substitution resulting in diminished sensitivity to feedback inhibition by nucleotides. The noncompetitive component of ADP inhibition of PRS1 was absent with S.M. PRS1 and ADP inhibition was purely competitive, with a Ki of 6.4 microM, APP-MP was a very poor inhibitor of S.M. PRS1, displaying uncompetitive characteristics and a Ki of 1.6 mM. These data indicate that APP-MP inhibits PRS1 with a strong element of noncompetitive inhibition and appears to interact specifically at the allosteric site used by ADP. These results contrast with those obtained with ADP, which has a strong component of ATP competitive inhibition and binds at the ATP site as well as at a second, allosteric, site.
Mol Pharmacol 1995 Apr
PMID:Inhibition of human 5-phosphoribosyl-1-pyrophosphate synthetase by 4-amino-8-(beta-D-ribofuranosylamino)-pyrimido[5,4-d]pyrimidine-5'- monophosphate: evidence for interaction at the ADP allosteric site. 772 42

We have investigated the effect of genotypes of apolipoprotein E (ApoE) on the pathologies found in Alzheimer's disease (AD) and its related gene expression in 38 aged human brains obtained from consecutive autopsied cases. ApoE2/3, -3/3, -3/4, and -4/4 were typed in those aged brains, with ApoE3/3 being most prevalent. The AD pathologies were undetectable in ApoE2/3 brains, but were frequently observed in the other ApoE groups. In ApoE3/3 brains, 55%, 34%, and 24% of the cortical sections examined showed senile plaques (SPs), neurofibrillary tangles (NFTs), and cerebral amyloid angiopathy (CAA), respectively. In ApoE4/4 brains, the SP formation was significantly higher. The ApoE genotype neither affected ApoE, APP, or tau mRNA level, nor the differential expression of the latter two. These results suggest that ApoE4/4 accelerates and ApoE2/3 decelerates the development of the AD pathologies in the aged brain, but this is not through alterations of the APP and tau gene expression.
Brain Res Mol Brain Res 1995 Mar
PMID:Apolipoprotein E genotype, Alzheimer's pathologies and related gene expression in the aged population. 777 5

In mammalian cells, the transmembrane beta-amyloid peptide precursor (beta-APP) undergoes a complex series of alternative proteolytic processing steps that result in the secretion of varying proportions of its extra-cellular domain (protease nexin II) and beta-amyloid peptide. The protein is also reinternalized and degraded in the endosomal-lysosomal system. The relative efficiencies of these competing processes determine the yield of beta-amyloid peptide. Several proteases have been implicated in this complex processing pathway, although none has been identified to date. The yeast secretory system contains proteases homologous to mammalian pro-hormone convertases and is susceptible to genetic manipulation. We therefore investigated the expression and processing of the beta-amyloid peptide precursors (beta-APP-695 and beta-APP-751) in Saccharomyces cerevisiae transformed with human beta-APP cDNA's. beta-APP (695 or 751) cDNA either with its authentic signal sequence or the yeast-derived prepro-alpha-factor leader, was inserted into a glucose-regulated expression vector and transfected into a protease-deficient yeast strain. In all instances, expression of beta-APP was about 1% of total protein. Protease protection studies indicated that either the natural human signal sequence or the alpha-factor leader sequence targetted beta-APP to the endoplasmic reticulum and inserted it with the amino-terminal domain in the lumen. All of the beta-APP fused to the alpha-factor leader proceeded to the trans-Golgi, where Kex2 endopeptidase removed the leader and released the normal amino-terminus of beta-APP. About one-half of the beta-APP was also cleaved at the "alpha-secretase" site in the middle of the beta-peptide sequence, 12 residues before the membrane-spanning sequence. A fraction of the alpha-secretase-cleaved beta-APP appeared in the culture medium; however, most of it associated with the exterior of the cells. The carboxyl-terminal fragments formed by cleavage at the alpha-secretase site accumulated in the membranes. Other proteolytic processes generated membrane-associated carboxyl-terminal fragments that also resembled those found in mammalian cells. These results indicate that the secretory system of S. cerevisiae possesses proteases with specificities similar to the mammalian enzymes that process beta-APP.
Cell Mol Biol Res 1994
PMID:The expression and processing of human beta-amyloid peptide precursors in Saccharomyces cerevisiae: evidence for a novel endopeptidase in the yeast secretory system. 786 29


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