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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The major pathological characteristic of Alzheimer's disease (AD) is the abnormal deposition of beta-amyloid peptide (A beta) in the brain. In some early onset cases, the disease develops because of mutations in the gene coding for beta-amyloid precursor protein (beta APP). However, the majority of AD families in the early onset subgroup are linked to a locus on chromosome 14. The genetic analysis and age of onset correlates of both the beta APP gene and the chromosome 14 locus are discussed. We speculate on the mechanisms by which the beta APP mutations cause the disease and discuss recent advances in beta APP processing that may be relevant to the pathogenesis of the late-onset (common) form of the disease. In addition, we review the association of the APOE locus with late-onset familial and nonfamilial disease. Further work is required to establish the effects of this locus on disease occurrence, age of onset, and progression. The molecular pathology of ApoE in relation to AD development and the identification of the chromosome 14 gene will greatly contribute to a general pathogenic model of AD, and will clarify the role of beta APP and its derivatives.
Mol Neurobiol
PMID:The molecular genetics of Alzheimer's disease. 788 92

Alzheimer's disease is a dementing disorder affecting increasingly large numbers of individuals in the aging population. The characteristic neuropathologic changes of Alzheimer's disease are the deposition of extracellular amyloid plaques, neurons containing neurofibrillary tangles, and neuronal cell loss. The A4 amyloid peptide is the major constituent of senile plaques. In addition to the A4 peptide, senile plaques contain a variety of molecular species, including proteoglycans and inflammatory components. The presence of proteoglycans in the amyloid deposits of Alzheimer's disease and of systemic amyloidoses suggests that these molecules play an active role in the pathogenesis of amyloidosis. However, the molecular mechanisms that lead to the codeposition of amyloid peptide with proteoglycans is still unknown. Recent evidence suggests that the metabolism of proteoglycans is altered in Alzheimer's disease patients. The acute-phase response observed in the brain of patients affected by Alzheimer's disease may be responsible for this effect. In this article, we discuss the role of proteoglycans in Alzheimer's disease, and the possible interactions between factors involved in brain inflammatory mechanisms and proteoglycans in the pathogenesis of Alzheimer's disease.
Mol Neurobiol
PMID:Proteoglycans and the acute-phase response in Alzheimer's disease brain. 788 2

Several factors have highlighted the vasculature in Alzheimer's disease (AD): Cerebral amyloid angiopathy (CAA) is common, amyloid fibrils emanate from the vascular basement membrane (VBM), and similar forms of beta-amyloid are found in vascular and parenchymal amyloid accumulations. The present article discusses the presence of microvascular pathology in AD. Microangiopathy, in addition to neurofibrillary tangles, senile plaques, and CAA, is a common pathologic hallmark of AD. VBM components are associated with amyloid plaques, and nonamyloidotic alterations of the VBM occur in brain regions susceptible to AD lesions. Also, intra-VBM perivascular cells (traditionally called pericytes), a subset of which share the immunophenotype of microglia and other mononuclear phagocytic system (MPS) cells, have been implicated in vascular alterations and cerebrovascular amyloid deposition. Perivascular and parenchymal MPS cells have access to several sources of the beta-amyloid protein precursor, including platelets, circulating white cells, and neurons. MPS cells would thus be ideally situated to uptake and process the precursor, and deposit beta-amyloid in a fashion analogous to that seen in other forms of systemic and cerebral amyloidoses.
Mol Neurobiol
PMID:Microvascular pathology and vascular basement membrane components in Alzheimer's disease. 788 5

Soluble beta/A4 amyloid protein precursor derivatives (APPs) in cerebrospinal fluid from infants, children, adults and aged individuals were treated with neuraminidase. In the samples from infants, reduction of molecular weight of APPs following neuraminidase treatment was significantly less than those from adults or aged individuals. Hyposialylation of beta/A4 amyloid protein precursor in infants may be relevant to a physiological role of this molecule in the development of the nervous system.
Brain Res Mol Brain Res 1994 Dec
PMID:Developmental changes of sialylation of soluble beta/A4 amyloid protein precursor derivatives in human cerebrospinal fluid. 789 17

The distributions of various immunohistochemical markers of neurofibrillary tangles (NFT) were compared to that of a normal nerve cell cytoskeletal marker, SMI32, in the inferior temporal cortex of Alzheimer brains and normal aged controls. NFT markers included antibodies to the microtubule-associated proteins tau, ubiquitin, or amyloid P component (AP). The results showed that, in our group of patients, the decrease of SMI32 immunoreactivity in the Alzheimer temporal cortex is paralleled by an increase in AP immunoreactivity in neurons and neurofibrillary tangles. This suggests that AP may play an important role in NFT formation or evolution in Alzheimer disease.
Mol Chem Neuropathol 1994 Jun
PMID:Immunoreactivity patterns in neurofibrillary tangles of the inferior temporal cortex in Alzheimer disease. 791 70

Evidence is presented that transcription of most of the early genes in the Streptomyces coelicolor A3(2) phage phi C31 is from a series of unusual promoters that depend on a function expressed early in the phi C31 lytic cycle. Primer extension analysis on the 5' ends of three early mRNAs, from samples prepared 10 min after induction of a thermosensitive phi C31 lysogen, showed that the 5' ends all mapped close to highly similar sequences, which are proposed to be an important part of phage-specific promoters. In a shotgun cloning experiment, a fragment containing one of these sequences strongly activated transcription of the xyIE reporter gene in plaques of a phi C31-derived promoter-probe vector. Another of the sequences was inserted into a xyIE-containing promoter-probe plasmid vector, and promoted xyIE expression only when the host was supporting the lytic cycle of phi C31. This suggested that a transcription factor needed for activity of the promoters was present only in phi C31-infected cells. Examination of published and unpublished phi C31 sequence data revealed several more sequences that closely resemble the conserved region of the characterized promoters. Most of these are found in positions close to apparent transcription start sites mapped previously by low-resolution S1 mapping. An overall consensus sequence for the conserved region suggests a general organization (though not a primary sequence) resembling that of promoters recognized in other bacteria by the sigma 54 form of RNA polymerase.
Mol Microbiol 1993 Sep
PMID:Multiple novel promoters from the early region in the Streptomyces temperate phage phi C31 are activated during lytic development. 793 40

A key pathological feature of Alzheimer's disease (AD) is the formation and accumulation of amyloid fibers within the neurophil as senile plaques and in the walls of cerebral and meningeal blood vessels. The major component is the 39 to 42 residue amyloid beta protein (A beta), which is an internal proteolytic fragment of the membrane-associated amyloid precursor protein. Aggregation of A beta into amyloid fibers that could be cytotoxic may be a factor in the AD-related neuronal loss. To understand the steps and molecular interactions involved in the transition from a soluble to fibrous form of A beta, and to test molecular models that postulate ion pairing between beta-strands, we have synthetized four peptides having substitutions in specific, charged residues. These included an A beta fragment, residues 11 to 25, and having histidine-to-aspartate replacements at positions 13 (H13D) and 14 (H14D), an aspartate-to-lysine at position 23 (D23K) and a 28-mer full-length extracellular domain where the positive charge cluster at His13-His14-Gln15-Lys16 was replaced by an uncharged Gly13-Gly14-Gln15-Gly16 (GGQG). Fourier-transform infrared spectroscopy and fiber X-ray diffraction determined that the H13D and H14D substitutions had negligible effect on beta-sheet formation, suggesting that these residues are not critical for the intramolecular interactions necessary for folding in the beta-conformation. However, negative-stain electron microscopy revealed that the loss of the His13 or His14 resulted in only protofilament formation, suggesting that these residues are involved in amyloid fibril assembly. By contrast, the D23K substitution virtually eliminated folding into a beta-sheet conformation, with appreciable secondary structure being detected only following extended incubation times. The complete absence of the centrally charged region GGQG arrested amyloid assembly at the protofilament stage and also reduced the stability of the beta-conformation, suggesting a contribution of Lys16 in maintaining secondary structure. While it has been conclusively demonstrated by previous investigations that amyloid formation is dependent to a large extent on hydrophobically driven interactions, our results indicate that charge-charge interactions function in concert with non-ionic interactions to stabilize the beta-sheet conformation and assembly of AD amyloid fibers.
J Mol Biol 1994 Nov 18
PMID:Conformation and fibrillogenesis of Alzheimer A beta peptides with selected substitution of charged residues. 796 23

Neuropeptide Y (NPY)-containing neurons are depleted in the cortices of individuals with Alzheimer disease (AD), yet spared in the striatum of patients with Huntington chorea. It is unknown whether this neuronal phenotype is inherently susceptible to the neurodegenerative processes that are a hallmark of AD. To study this question, the murine trisomy 16 model of Down syndrome and Alzheimer disease was investigated. Since trisomic fetuses die in utero, studies were carried out on primary cultures of dissociated cortical neurons. These were prepared from 15-d gestational trisomy 16 fetuses and their littermate euploid controls, and examined by immunocytochemical staining for neuropeptide Y at 7 and 12 d in vitro. Trisomy 16 neurons were also grown on euploid glial carpets, whereas euploid neurons were grown on trisomic glia. The results demonstrate a significant increase in the number of NPY neurons and a stunting in the dendritic arbor of these neurons in trisomic vs euploid cortex. Both of these parameters could be normalized by direct contact with euploid glia. When euploid cortex was plated on trisomic glia, the number of NPY neurons and their morphology were altered so that they began to resemble trisomic NPY cortical neurons. These results indicate a dysregulation of NPY neuronal expression and differentiation in trisomy 16 cortex that are modifiable by interaction with euploid glia and imply an abnormal trophic (glial) environment in trisomic cortex.
Mol Chem Neuropathol 1994 Aug
PMID:Neuropeptide Y immunoreactive neurons in murine trisomy 16 cortical cultures. Plasticity of expression and differentiation. 799 28

We have investigated protein-DNA interactions in the proximal promoter of the human amyloid precursor protein (APP) gene in temporal lobe neocortical nuclei isolated from control and Alzheimer disease (AD) affected brains. We report that the human APP 5' promoter sequence from -203 to +55 bp, which has been previously reported to contain essential regulatory elements for APP gene transcription, lies in a deoxyribonuclease I, micrococcal nuclease- and restriction endonuclease-sensitive, G+C-rich nucleosome-free gap flanked both 5' and 3' by typical nucleosome structures. As analyzed by electrophoretic mobility shift assay, this extended internucleosomal linker DNA is heavily occupied by nuclear protein factors, and interacts differentially with nuclear protein extracts obtained from HeLa and human brain neocortical nuclei. This suggests that the chromatin conformation of the APP gene promoter may vary in different cell types, and may correlate with differences in APP gene expression. Human recombinant transcription factors AP1, SP1 and TFIID (but not AP2 or brain histones H1, H2B and H4) interact with the -203 to +55 bp of the human APP promoter sequence. Only minor differences were observed in the chromatin structure of the immediate APP promoter between non-AD and AD affected neocortical nuclei, suggesting either that post-transcriptional processes, or that regulatory elements lying elsewhere in the APP gene may be important in the aberrant accumulation of the APP gene product.
Brain Res Mol Brain Res 1994 Mar
PMID:Protein-DNA interactions in the promoter region of the amyloid precursor protein (APP) gene in human neocortex. 801 72


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