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)

Deposits of beta-amyloid are one of the main pathological characteristics of Alzheimer's disease. The beta-amyloid peptide (or beta/A4) constituent of these deposits is derived from the beta-amyloid precursor protein (beta APP), which is expressed in several isoforms. It has been suggested that an imbalance in the normal ratio between the Kunitz protease inhibitor (KPI)-containing beta APPs versus the non containing forms could result in altered processing of beta APP and progressive beta/A4 deposition. We have studied the expression of four beta APP isoforms in the rat brain after intracerebroventricular application of kainic acid. Increased levels of the KPI-containing beta APP and GFAP mRNAs were observed in tissues surrounding areas of neuronal damage. A parallel increase of beta APP and GFAP immunoreactivity was observed in reactive astrocytes in these areas. These results suggest that the normal ratio of beta APP isoforms may be profoundly altered as a result of neuronal damage and that non-neuronal cells may respond to neuronal injury by increased expression of the KPI-containing beta APP isoforms.
Brain Res Mol Brain Res 1993 Jan
PMID:Increased levels of the Kunitz protease inhibitor-containing beta APP mRNAs in rat brain following neurotoxic damage. 838 8

To study cell type-specific regulation of the gene for amyloid precursor protein (APP), we have analysed the human APP promoter for transcriptional activity and interaction with nuclear proteins in the neuronal cell line NG108-15. Sequences from -203 to +104 were sufficient for promoter function and regulatory elements within this region (-128 to -63) were identified by DNase I protection experiments. These results suggest that essentially the same proximal elements are recognized by nuclear factors from both neuronal and nonneuronal cells.
Brain Res Mol Brain Res 1993 Aug
PMID:Expression of amyloid precursor protein in a neuronal cell line: functional activity of proximal regulatory elements. 841 70

In cultured astrocytes, all three major transcripts of beta-amyloid precursor protein (APP) were expressed with the ratio for APP695, APP751 and APP770 isoform mRNAs being 1:4:2. In comparison with controls, treatment of astrocytes with transforming growth factor-beta 1 (TGF-beta 1) produced about 6 fold increase in total APP mRNA, while elevation in the interleukin-1 beta (IL-1 beta) treated group was small and may relate to the mitogenic effect of IL-1 beta on astrocytes. Treatment of astrocytes with cytokines also produced marked changes in the upregulation in expression of different APP isoforms. The net increase in mRNAs of KPI-containing isoforms APP751 and APP770 was relatively more than for the APP695 isoform. This phenomenon was mainly related to the differences in the expression of KPI-containing APP isoforms and APP695 isoform in the controls. The present findings provide further evidence for the involvement of astrocytes in a cascade of events leading to the development of senile plaques in Alzheimer's disease and Down's syndrome.
Brain Res Mol Brain Res 1993 Aug
PMID:Regulation of beta-amyloid precursor protein isoform mRNAs by transforming growth factor-beta 1 and interleukin-1 beta in astrocytes. 841 71

The phage growth limitation (Pgl) system of Streptomyces coelicolor A3(2) was shown to be specific to phi C31 homo-immune phages, and to be absent from the closely related strain Streptomyces lividans. A 16 kb fragment of S. coelicolor A3(2) DNA was isolated which complemented the Pgl- phenotype of J1501, a pgl mutant derivative of the Pglts S. coelicolor strain M130. The cloned DNA complemented only half of the available pgl mutants, which therefore represented at least two groups, designated Pgl class A and class B strains. It follows that more than one kind of high-frequency genetic event can lead to the Pgl- phenotype. Crosses between class A and class B strains yielded high frequencies of Pgl+ recombinants. Crosses between strains of the same class gave no Pgl+ recombinants. The cloned DNA was altered by deletion or apparent point mutation upon passage through the two class B strains tested, such that it was no longer capable of complementing class A strains. This accumulation of mutations might suggest that the expression of the cloned DNA is toxic to at least some class B strains. The nature of the genetic instability associated with the Pgl system was not detectable by Southern blot analysis.
Mol Microbiol 1993 Jan
PMID:Genetic analysis of the phi C31-specific phage growth limitation (Pgl) system of Streptomyces coelicolor A3(2). 844 35

The beta/A4 region of the amyloid precursor protein (APP) accumulates in brains of victims of Alzheimer disease (AD) where it is a major component of senile plaques. We examined the pathophysiological consequences of overexpression of the beta/A4-C-terminal DNA in PC12 cells. Serum-free conditioned media (SFCM) from positive transfectants stimulated control PC12 cells to extend neurites and increase in size. Unlike the factor that affected cell size, neurite lengthening activity was significantly decreased after immunoabsorption with anti-beta/A4 monoclonal antibodies (MAb) and changes in pH. The data support the view that among the consequences of beta/A4-C-terminal DNA overexpression in PC12 cells is the release of factors that stimulate nontransfected cells to undergo morphological transformations that include differentiation to a neuronal phenotype. It is hypothesized that similar activities that may contribute to the molecular pathophysiology of the disorder may be present in the AD brain.
Mol Chem Neuropathol
PMID:PC12 cells release stimulatory factors after transfection with beta/A4-C-terminal DNA of the Alzheimer amyloid precursor protein. 846 96

The functional and structural consequences of altering the position of the negatively charged aspartate residue at the base of the specificity pocket of trypsin have been examined by site-directed mutagenesis, kinetic characterization and crystallographic analysis. Anionic rat trypsin D189G/G226D exhibits a high level of catalytic activity on activated amide substrates, but its relative preference for lysine versus arginine as the P1 site residue is shifted by 30 to 40-fold in favor of lysine. The crystal structure of this variant has been determined in complexes with BPTI (bovine pancreatic trypsin inhibitor), APPI (amyloid beta-protein precursor inhibitor domain) and benzamidine inhibitors, at resolutions of 2.1 A, 2.5 A and 2.2 A, respectively. Asp226 bridges the base of the specificity pocket with its negative charge partially buried by interactions made with Ser190 and Tyr228. An equal reduction in the affinity of the variant enzyme for Arg and Lys substrates is attributable to a decreased electrostatic interaction of each ligand with the relocated aspartate residue. Comparison of structural and functional parameters with those of wild-type trypsin suggests that direct hydrogen-bonding electrostatic contacts in the S1 site do not significantly improve the free energy of substrate binding relative to indirect water-mediated interactions. The conformation adopted by Asp226, as well as by other adjacent side-chain and backbone groups, depends upon the ligand bound in the primary specificity pocket. This structural flexibility may be of critical importance to the retention of catalytic activity by the variant enzyme.
J Mol Biol 1993 Apr 05
PMID:Relocating a negative charge in the binding pocket of trypsin. 847 42

We have performed a biochemical mapping of the neurofibrillary degeneration in all cortical areas of Alzheimer patients, using the immunological quantification of pathological tau 55, 64, and 69. These abnormally phosphorylated proteins, which are the basic components of PHF, are reliable markers of the degenerating process in Alzheimer disease. Here, we report our biochemical findings on a brain from a 90-yr-old woman with an 8-yr history of Alzheimer disease who exhibited dramatic and general cortical involvement. The detection of these markers was very high in all Brodmann areas, even in primary motor, somatosensory, or visual cortex. This case report contrasts with other studies, which suggested that a more virulent disease process is generally associated with an early onset and argues for the heterogeneity of the disease. Moreover, we show here that the immunodetection of abnormal tau proteins using the western blot method is a precise, reliable, and reproducible way to quantify the degenerating process in AD.
Mol Chem Neuropathol 1993 Apr
PMID:General cortical involvement in a late-onset case of Alzheimer disease. A biochemical approach by quantitation of abnormal tau proteins. 850 1

In order to study the expression of beta-amyloid precursor protein (APP) isoforms during neuronal degeneration we have used the rat superior cervical ganglia (SCG) as an experimental model. In the neonate these sympathetic ganglia are nerve growth factor (NGF) dependent and in vivo administration of anti-NGF antiserum results in exaggerated neuronal degeneration. Analysis of APP mRNA transcripts in the SCG, following NGF deprivation, revealed a coincident decrease in APP695 and augmentation of APP751/770. These changes were specific to the SCG and were not seen in sensory ganglia. Subsequent in vitro studies, using primary dissociated cultures of sympathetic or cortical neurones, confirmed these changes in APP gene expression during neuronal degeneration. These observations may have important implications for the generation of beta-amyloid in Alzheimer's disease.
Brain Res Mol Brain Res 1993 Mar
PMID:NGF deprivation and neuronal degeneration trigger altered beta-amyloid precursor protein gene expression in the rat superior cervical ganglia in vivo and in vitro. 851 May 4

The cellular localization of amyloid beta-protein precursor (beta APP) RNA transcripts was studied by in situ hybridization histochemistry in normal, heterozygous and homozygous weaver (wv) mutant mice, which lose midbrain dopamine (DA) neurons, cerebellar granule cells, and Purkinje cells. The beta APP gene is located at the distal end of mouse chromosome (MMU) 16, on which the wv locus has been assigned as well. Transcripts encoding isoforms beta APP695, beta APP714 and beta APP751 were present in several different brain areas of normal (+/+) mice, including hippocampus, substantia nigra (SN) pars compacta and cerebellum. The same transcripts were progressively reduced in homozygous weaver (wv/wv) SN, in correlation with DA neuron loss. The beta APP770 species--normally seen in striatum and not SN--was present in the mutant striatum. There were not any obvious changes in beta APP expression in the nigrostriatal system of weaver heterozygotes (wv/+). In normal cerebellum, Purkinje cells showed very high levels of hybridization signal for beta APP695, beta APP714 and beta APP751 RNA transcripts, and a moderate signal for the beta APP770 species. In weaver heterozygotes and homozygotes, Purkinje cells, which are typically not arranged in a monolayer, showed strong hybridization signal. No changes in beta APP mRNAs were observed in brain areas other than the cerebellum and ventral midbrain of weaver mutants. These findings suggest that the decreased beta APP gene expression seen in the cerebellum and SN of weaver mutants most likely represents an epiphenomenon of the regional nerve cell loss and, therefore, the wv gene defect on MMU 16 does not seem to influence the expression of the closely linked beta APP gene in brain areas outside the nigrostriatal pathway and cerebellar cortex.
Brain Res Mol Brain Res 1993 Mar
PMID:Regional distribution of the alternatively spliced isoforms of beta APP RNA transcript in the brain of normal, heterozygous and homozygous weaver mutant mice as revealed by in situ hybridization histochemistry. 851 May 6

The amyloid beta-protein precursor (APP) gives rise to the A beta peptide, which is deposited in the brains of patients with Alzheimer's disease and Down's syndrome. Overexpression of APP due to a third copy of the gene appears to correlate with very early onset of Alzheimer's disease neuropathology in the brains of Down's syndrome patients. Thus, the identification of the factors involved with transcriptional regulation of the APP gene could provide critical clues regarding the events leading to the formation of amyloid deposits. An overlapping AP-1/AP-4 site in the proximal promoter region (-39 to -49) of the human APP gene has previously been shown to increase transcription 4-fold. Here we identify the factor binding specifically to this element as the upstream stimulatory factor USF, unrelated to the c-fos/c-jun complex or the AP-4 factor. In vitro transcription and co-transfection studies show that USF activates transcription from the APP promoter and that the AP-1/AP-4 element participates in this activation. Modulation of APP expression via regulation of USF could potentially ameliorate the production of Alzheimer-augmented beta-amyloid.
Hum Mol Genet 1995 Sep
PMID:The upstream stimulatory factor functionally interacts with the Alzheimer amyloid beta-protein precursor gene. 854 35


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