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)

We have used nonisotopic in situ hybridization techniques with biotinylated junctional oligonucleotide probes to study expression of amyloid precursor protein (APP) 695 and 751 mRNA in the hippocampal formation of Alzheimer's disease. Both mRNAs are strongly expressed in neurons of the hippocampal formation, particularly in the dentate gyrus granule cells and the pyramidal neurons of CA3. The patterns of expression of neither APP695 nor APP751 mRNA correlate well with the stereotyped topography of neurofibrillary tangles or senile plaques, which occur primarily in CA1 and subiculum. We double-labeled in situ sections with immunohistochemical reagents for neurofibrillary tangles or senile plaques. Neurons that contain neurofibrillary tangles continue to express APP mRNA. The level of APP695 and APP751 was measured semiquantitatively by optical density measurements in neurons that were close to (within 25 microns) or father from a senile plaque (more than 100 microns). There was no increase in expression in neurons in the immediate microenvironment of senile plaques. Our results suggest that no major change in distribution or type of APP mRNA accompanies neurofibrillary tangle or senile plaque development.
Brain Res Mol Brain Res 1993 May
PMID:Nonisotopic in situ hybridization of amyloid beta protein precursor in Alzheimer's disease: expression in neurofibrillary tangle bearing neurons and in the microenvironment surrounding senile plaques. 768 84

Alzheimer's disease and cognitive impairment in rats has been associated with an increase in the percentage of amyloid precursor protein (APP) containing the KPI domain. It has recently been reported that retinoic acid (RA) is capable of increasing the levels and altering the splicing ratio of APP in cultured SH-SY5Y cells. The effects of peripherally administered RA (64 or 640 micrograms/kg; i.p.; q.d.) on the abundance of APP, the ratio of the three major isoforms, and the relative abundance of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) were determined by rtPCR in the hippocampus of aged rats. Corresponding changes in choline acetyltransferase (ChAT) activity were also measured. Vehicle (DMSO) treated rats exhibited a 2 x (P < 0.01) increase in total APP and an 8 x (P < 0.001) decrease in the cyclophilin transcript. In addition, DMSO increased the percentage of APP 695 from 89% in saline treated rats to 94%. Treatment of RA in DMSO decreased the accumulation of total APP relative to cyclophilin at both the low (6.4 x; P < 0.01) and high (8 x; P < 0.05) dosages when compared to DMSO treated rats. Furthermore, the level of APP-695 decreased to 82% with low dosage of RA and 75% at high dosage of the total APP transcripts. No significant change in either NGF, NT-3, or BDNF transcripts were observed following low or high dosage RA administration relative to cyclophilin RNA nor was a change in ChAT activity detected at either of the dosages tested.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1993 May
PMID:Altered levels and splicing of the amyloid precursor protein in the adult rat hippocampus after treatment with DMSO or retinoic acid. 768 85

The proteases that cleave amyloid precursor protein (APP) leading to generation of amyloid A beta peptide are potential targets for therapeutical intervention of Alzheimer disease. We have been pursuing the identification and characterization of these proteases using as probes the fluorogenic substrates encompassing the cleavage sites of APP that we described recently (Wang, G. T., Krafft, G. A. [1992] Bioorg. Med. Chem. Lett. 2, 1665). This article describes results of experiments designed to examine the effect of Ca(2+) on the cleavage of these substrates by human brain extracts. Fluorogenic substrates encompassing either the N-terminal amyloidogenic cleavage site or the secretory cleavage site were synthesized in five formats with various peripheral residues. Incubation with extracts from normal brain tissue revealed that more negatively charged amyloidogenic substrates were less reactive and exhibited larger rate enhancement in the presence of Ca(2+). The results imply that Ca(2+) stimulation of substrate cleavage by brain proteases occurs primarily as a result of Ca(2+)-substrate interactions, and caution against interpretations that invoke the involvement of Ca(2+)-stimulated proteases in A beta formation.
Mol Chem Neuropathol
PMID:Cleavage of fluorogenic substrates for APP-processing proteases by human brain extracts. Ca(2+)-substrate interaction is responsible for Ca2+ stimulation of the neural protease activity. 770 8

Deposition of amyloid fibrils in the brain is a histopathologic hallmark of Alzheimer disease (AD) and beta-amyloid protein (A beta), the principal component of amyloid fibrils, has been implicated in the neuropathogenesis of AD. In the present study, we first developed an in vitro model of A beta-induced neurodegeneration using human fetal brain-cell cultures and then tested the hypothesis that cytokines modulate A beta-induced neurodegeneration. When brain-cell cultures were exposed to A beta, marked neuronal loss (60% of neurons by microscopic assessment) and functional impairment (i.e., reduction in uptake of [3H]gamma-aminobutyric acid) were observed after 6 d of incubation. A beta-induced neurodegeneration was dose-dependent with maximal effect at 100 microM. Although interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-alpha had a nominal effect, both the beta 1 and beta 2 isoforms of transforming growth factor-beta dose-dependently protected > 50% of neurons against A beta-induced injury. IL-4 also proved to be neuro-protective. A beta-induced neurodegeneration was accompanied by microglial cell proliferation and enhanced release of IL-1, IL-6, and TNF-alpha. These findings are consistent with the emerging concept that AD is an inflammatory disease and may lead to new therapeutic strategies aimed at reducing A beta-induced neurotoxicity.
Mol Chem Neuropathol
PMID:Transforming growth factor-beta protects human neurons against beta-amyloid-induced injury. 770 6

To understand the possible role of amyloid precursor protein (APP) in human lymphocytes, and the regulation of APP gene expression in this cell type, we determined levels of cellular APP protein and of mRNA in human T-cell-derived Jurkat cells that were treated with lectin, phorbol ester, and calcium ionophore. We also related these levels to cell aggregation and adhesion. Cell-cell aggregation and cell-plastic adhesion were observed over a 24-h period after incubating cells for 2 h with phytohemagglutinin or phorbol myristate acetate. Cells treated with a calcium ionophore showed no aggregation or adhesion. Western blots indicated no obvious alteration in the level of cellular APP with different treatments. Northern blots showed a significant transient increase of APP mRNA after incubation with the calcium ionophore, whereas phorbol ester treatment showed a slight increase of APP mRNA. We analyzed the level of APP mRNA in human peripheral T cells which had been separated from peripheral lymphocytes. The level increased transiently by up to threefold after treatment with calcium ionophore plus phorbol esters. These data suggest that cell-cell aggregation and cell-matrix adhesion by human lymphocytes are not associated with an increased level of cellular APP protein or of mRNA.
Mol Chem Neuropathol
PMID:Induction of gene expression of amyloid precursor protein (APP) in activated human lymphoblastoid cells and lymphocytes. 770 10

Familial (autosomal dominant) Alzheimer's disease (FAD) is a genetically heterogeneous disorder. Mutations in exons 16 and 17 of the amyloid beta-protein precursor (beta PP) gene currently account for less than 2% of FAD kindreds. No known defect in beta PP quantity, structure, or processing accounts for disease-associated beta-amyloid deposition in the majority of early-onset FAD kindreds. Only two out of a sample of 48 pedigrees (particularly the early onset FAD 4 kindred) contributed noticeably to evidence of linkage at the D21S16/13 and S1/S11 loci in the chromosomal region 21q21 [75]. Many early onset FAD pedigrees (including the FAD 1 and FAD 4 kindreds) show strong evidence of linkage to markers in the chromosome 14q24.3 region. Patients with trisomy 21 (Down's syndrome, DS) virtually always develop a histopathological phenotype indistinguishable from FAD, presumably on the basis of increased beta PP gene dosage and transcription. Whereas no beta PP gene duplication has been found in FAD, other mechanisms that augment beta PP production by effects at the transcriptional level could explain some FAD cases. Here, we report that cultured fibroblasts from affected members of the FAD 1 pedigree show a approximately 1.9 fold increase (P = 0.007) in beta PP mRNA levels compared to unaffected members when the cells are grown under stressed conditions in 0.5% serum. The elevated levels of beta PP mRNA in cells cultured in 0.5% serum also cosegregate with haplotypes in the 14q24.3 region when analyzed by linkage methods (LOD score = 3.26 at theta = 0.001). This is the chromosomal region to which FAD in this family has previously been mapped. As expected, fibroblasts from patients with DS used as a control show a similar beta PP mRNA increase. Fibroblasts from the FAD 4 pedigree did not show this defect under the conditions utilized here. beta PP and A beta protein levels were determined quantitatively after metabolic labeling and immunoprecipitation and found to increase 2.0 and 2.5 fold, respectively, in the fibroblasts from affected FAD 1 members. Finally, transient transfections of a beta PP promoter/chloramphenicol acetyl transferase reporter gene construct demonstrated a approximately 3-4 fold increase in beta PP promoter activity in affected fibroblasts from the FAD 1 but not the FAD 4 pedigree. Taken together, these data raise the possibility that an increase in beta PP transcription may underlie the AD phenotype in at least some of the chromosome 14-linked FAD families.
Brain Res Mol Brain Res 1995 Feb
PMID:Beta APP mRNA transcription is increased in cultured fibroblasts from the familial Alzheimer's disease-1 family. 772 30

Prolonged exposure of cultured cortical cells or cultured cerebellar granule cells to the residue 25-35 fragment of beta-amyloid peptide (beta AP), beta AP(25-35), induced neuronal apoptosis, as revealed by morphological analysis, fluorescent chromatin staining, and immunodetection of oligonucleosomes released from the nucleus into the cytoplasm. beta AP(25-35)-induced apoptosis was insensitive to ionotropic glutamate receptor antagonists but was substantially attenuated by the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid. The neuroprotective action of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid was antagonized by (RS)-alpha-methyl-4-carboxyphenylglycine and was mimicked by (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (a selective agonist of mGluR2 and -3 subtypes) and by L-2-amino-4-phosphobutanoate and L-serine-O-phosphate (selective agonists of mGluR4, -6, and -7 subtypes). However, whereas all of these drugs behaved as neuroprotectants in cultured cortical cells, only L-2-amino-4-phosphobutanoate and L-serine-O-phosphate [and not (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine] reduced beta AP(25-35)-induced apoptosis in cultured cerebellar granule cells. The neuroprotective activity of mGluR agonists may be related to their ability to inhibit membrane Ca2+ conductance, because drugs that block voltage-sensitive Ca2+ channels, such as nimodipine or Co2+, could also attenuate beta AP(25-35)-induced apoptosis.
Mol Pharmacol 1995 May
PMID:Activation of metabotropic glutamate receptors protects cultured neurons against apoptosis induced by beta-amyloid peptide. 774 77

Cortical M1 muscarinic receptor-G-protein coupling, high-affinity, guanine nucleotide-sensitive agonist binding (Flynn et al., 1991; Warpman et al., 1993) and muscarinic receptor-stimulated [3H]PIP2 hydrolysis (Ferrari-DiLeo and Flynn, 1993) are known to be defective in Alzheimer disease. Whether this defect reflects an alteration in the M1 muscarinic receptor, its respective guanine nucleotide binding (G) protein or both is not known. This study compares the number and both basal and muscarinic receptor-mediated function of G-proteins in synaptosomal membranes from cerebral cortical samples of age-matched control subjects and Alzheimer disease patients. Immunoblotting with anti-G alpha q/11 and anti-G beta antibodies demonstrated no alteration in the number of these G-protein subunits in Alzheimer disease. Basal [35S]GTP gamma S binding and hydrolysis of [gamma-32P]GTP by high-affinity GTPase also were not significantly altered in Alzheimer disease compared to control membrane samples. However, muscarinic agonist-stimulated GTP gamma S binding and GTP hydrolysis were significantly reduced (80-100%) in Alzheimer disease cortical samples. Diminished agonist-stimulated GTP gamma S binding and GTP hydrolysis correlated with the loss of guanine nucleotide-sensitive, high-affinity agonist binding (KL/KH) ratio) to the M1 receptor subtype. These data provide further evidence for the loss of muscarinic receptor-G protein coupling in Alzheimer disease and support the hypothesis that muscarinic receptor-mediated cortical activation may be compromised in Alzheimer disease.
Mol Chem Neuropathol 1995 Jan
PMID:Attenuation of muscarinic receptor-G-protein interaction in Alzheimer disease. 775 48

1. Alzheimer's disease is characterized by the deposition in the brain of extracellular amyloid plaques and vascular deposits consisting mostly of amyloid beta-peptide (A beta). A beta, a polypeptide of 39-43 amino acids (M(r), approximately 4 kDa), is derived proteolytically from a family of proteins of 695-770 amino acids (M(r), approximately 110-140 kDa) called beta-amyloid precursor protein (beta APP). 2. beta APP, an integral membrane glycoprotein, is extensively posttranslationally modified within the endoplasmic reticulum (ER) and various Golgi compartments. beta APP is cleaved by proteases in either the trans-Golgi network or the post-Golgi apparatus and then secreted as a truncated soluble form into the conditioned media of cultured cells and cerebrospinal fluid samples from human subjects. beta APP can be processed either by an antiamyloidogenic secretory pathway or by an endosomal/lysosomal pathway. 3. I studied the effect of two ionophores on the processing of beta APP in cultured cells. Monensin and, in some cases, ammonium chloride increase the intracellular accumulation of beta APP in several cell lines and may alter its processing. Monensin, which had the most consistent effects, also inhibited secretion of beta APP in a differentiated (growth factor mediated) cell line. Nigericin, with greater K+ selectivity, was less able to alter the accumulation and possible processing of the protein. 4. These results suggest that the increase in the accumulation of intracellular beta APP observed after treating cells with ionophores has some specificity. The selective effect of these ionophores on the metabolism of beta APP may provide a model system to analyze the pathways for studying maturation, secretion, and degradation of beta APP.
Cell Mol Neurobiol 1994 Aug
PMID:Effect of ionophores on the processing of the beta-amyloid precursor protein in different cell lines. 778 40

The beta amyloid peptide which accumulates within the brains of patients with Alzheimer's disease (AD) is proteolytically derived from a precursor protein (beta PP). We established and characterized four stably transformed human neuroblastoma cell lines which conditionally expressed a partial beta PP fusion protein (amino-17 residues+carboxyl-99 residues; S beta C). Conditional expression of S beta C was achieved using a tetracycline-responsive promoter system. Expression of this fusion protein in one of the cell lines resulted in pronounced cytotoxicity. Addition of n6,O2'-dibutyryl adenosine 3',5'-cyclic monophosphate and/or fetal bovine serum to the culture medium of this cell line further elevated the level of S beta C expression and enhanced the associated cytotoxicity. Conditioned medium, acquired from cells expressing S beta C, was not cytotoxic. These findings suggest that modulation of beta PP expression and/or metabolism can have cytotoxic consequences. This is the first report of cytotoxic effects mediated by conditional expression of a beta PP derivative. This immortal cell line provides a unique opportunity to screen for complementary DNAs which suppress this toxicity. Such cDNAs could help elucidate the processes underlying S beta C mediated cytotoxicity which in turn could further our understanding of the pathogenesis of AD and could also provide additional candidate genes for various forms of familial AD.
Brain Res Mol Brain Res 1994 Oct
PMID:Cytotoxicity mediated by conditional expression of a carboxyl-terminal derivative of the beta-amyloid precursor protein. 785 49


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