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Biomedical subjects

B Cordell

Publications and source records attributed to B Cordell.

At least 55 records · Page 3Linked to original sources
PubMed1994

Development of a monoclonal antibody specific for the COOH-terminal of beta-amyloid 1-42 and its immunohistochemical reactivity in Alzheimer's disease and related disorders.

The beta-amyloid peptide (beta AP) has been characterized by protein sequencing techniques as a 39-43 amino acid protein with heterogeneous COOH-termini. Controversy exists regarding the predominant form of beta AP in neuritic plaques (NP) and cerebral vasculature of Alzheimer's disease (AD) brain. A monoclonal antibody was developed that selectively recognizes the free COOH-terminal of beta AP 1-42 but not beta AP species with shorter or longer COOH-termini. Brain sections from AD and related disorders were examined using this antibody. In AD samples, the antibody stained diffuse amyloid and NP cores, many intraneuronal and extraneuronal neurofibrillary tangles (NFT), but not cerebrovascular amyloid. Pick and Lewy bodies lacked immunoreactivity. These findings suggest that beta AP 1-42 is present in early and mature amyloid deposits and NFT, but that species of beta AP other than 1-42 comprise human vascular deposits.

Adult↗
PubMed1993

Transgenic mice expressing human beta-APP751, but not mice expressing beta-APP695, display early Alzheimer's disease-like histopathology.

Mice transgenic for the 751 amino acid isoform of the human beta-amyloid precursor protein (beta-APP) driven by the rat neuron specific enolase (NSE) promoter (NSE:beta-APP751) show features of early Alzheimer's disease (AD) pathology. These features, which were evident in multiple pedigrees, include: 1) preamyloid deposits which stain with antibodies that are specific for the beta-amyloid peptide and stain AD amyloid deposits and plaques, and 2) neuronal soma and processes which stain with an antibody (Alz50) that detects abnormal isoforms of tau which are characteristic of AD. The quality and distribution of both types of immunoreactivity revealed in the NSE:beta-APP751 mouse brains most closely resemble those seen in brains of young adults with Down's syndrome. Both structures are rarely, if ever, observed in brains from mice transgenic for the 695 amino acid isoform of beta-APP (NSE:beta-APP695) or in wild type mice.

Aging↗
PubMed1993

Total quality management and quality assurance: discussing the differences.

Total Quality Management and Continuous Quality Improvement have become the "buzz" phrase for the 1990s. Everyone seems to be jumping on the band wagon. But what is it, and is it right for your organization? We believe that Total Quality Management is superior to many Quality Assurance programs currently in use. There are, however, many considerations to take into account before implementing a Total Quality Management program. The purpose of this article is to explain the pros and cons of Total Quality Management and standard Quality Assurance programs and to compare and contrast these two approaches. This article focuses on barriers to successful implementation and presents several questions organizations can utilize in assessing readiness for a quality management program.

Humans↗
PubMed1992

Expression cloning of neurotrophic factors using Xenopus oocytes.

We have explored the potential for cloning novel neurotrophic factor cDNAs via assay of neurotrophic activities following expression in Xenopus oocytes. In this report, we describe the successful application of the method to tract rat ciliary neurotrophic factor (CNTF) activity from mRNA purified from cultured cells and from mRNA synthesized by in vitro transcription of a cDNA library. Rat C6 glioma cells, which had been previously shown to have CNTF-like activity (Westermann et al., 1988), were used as source material. We tested protein extracts of C6 cells using an in vitro assay of primary neurons from the chick ciliary ganglion (CCG assay) and detected a CNTF-like activity. RNA isolated from C6 cells was shown to direct the synthesis of the activity following microinjection into Xenopus oocytes and one-step fractionation of Xenopus extract. C6 mRNA was size-fractionated, and fractions encoding CNTF-like activity were cloned into a lambda phage vector at a site distal to a T7 promoter. Synthetic RNA transcribed from total library DNA was injected into Xenopus oocytes, and a CNTF-like activity in the oocyte extract was detected by the CCG assay. Further fractionation of library clones narrowed the presence of the clone encoding the CNTF-like activity to a pool containing 20,000 members. The presence of a full-length CNTF cDNA clone in this pool and partial clones in other pools was confirmed by Polymerase Chain Reaction (PCR) using oligonucleotides from the rabbit CNTF cDNA (Lin et al., 1989) as primers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Sequence analysis and editing of the phosphoprotein (P) gene of rinderpest virus.

We have cloned the cDNA of the phosphoprotein (P) gene of the virulent (Kabete "O") strain of rinderpest virus and provided a comparative analysis of its sequence with that of the P genes of measles, canine distemper, and phocid distemper viruses. The gene encodes two overlapping open reading frames of 1521 and 531 nucleotides. Use of the first ATG would produce a P polypeptide of 507 amino acids with a calculated molecular weight of 54,344. The second ATG would produce a C polypeptide of 177 residues with a predicted molecular weight of 19,927. In addition, the insertion of a G residue at position 740 generates an alternative mRNA potentially encoding the V polypeptide of rinderpest virus. The homology comparisons in P amino acid sequences between rinderpest and measles, between rinderpest and canine distemper, and between rinderpest and phocid distemper viruses are 60, 44, and 46%, respectively. A four-way comparison shows an identity of 34%. Similar homology comparisons with the C amino acid sequence between rinderpest and measles, rinderpest and canine distemper, and rinderpest and phocid distemper viruses are 56, 42, and 40%, respectively. A homology of 31% is found in a four-way comparison for the C polypeptide. From the point of the insertion of the G residue, there is a homology of 78% between the V polypeptides of rinderpest and measle viruses.

Amino Acid Sequence↗
PubMed1991

Alzheimer's disease: beta-amyloid precursor protein expression in plaques varies among cytoarchitectonic areas of the medial temporal lobe.

The anatomic distributions of beta-amyloid peptide (beta AP) and beta-amyloid precursor protein (beta APP) in the medial temporal lobe were examined with immunocytochemistry in Alzheimer's disease. beta AP-containing plaques were found most frequently in the cortical and basal regions of the amygdala, and in the hippocampal CA1, subiculum, and dentate molecular layer. beta APP expression in plaques was found in a similar distribution, with some, but not all beta AP plaques also showing beta APP. In the cortical and basal amygdala, some cases showed beta APP in the centers of plaques, whereas in the hippocampus, all cases displayed beta APP mainly in plaque neurites. The lateral regions of the amygdala contained mainly diffuse beta AP plaques which had little beta APP. These findings suggest that although beta APP expression and beta AP deposition generally colocalize, processing of beta APP may vary among closely interconnected anatomic regions.

Adult↗
PubMed1991

Formation of beta-amyloid protein deposits in brains of transgenic mice.

Deposits of beta-amyloid are one of the main pathological characteristics of Alzheimer's disease. The beta-amyloid peptide constituent (relative molecular mass 4,200) of the deposits is derived from the beta-amyloid precursor protein (beta-APP) which is expressed in several different isoforms. The two most prevalent beta-APP isoforms are distinguished by either the presence (beta-APP751) or absence (beta-APP695) of a Kunitz serine protease inhibitor domain. Changes in the abundance of different beta-APP messenger RNAs in brains of Alzheimer's disease victims have been widely reported. Although these results have been controversial, most evidence favours an increase in the mRNAs encoding protease inhibitor-containing isoforms of beta-APP and it is proposed that this change contributes to beta-amyloid formation. We have now produced an imbalance in the normal neuronal ratio of beta-APP isoforms by preparing transgenic mice expressing additional beta-APP751 under the control of a neural-specific promoter. The cortical and hippocampal brain regions of the transgenic mice display extracellular beta-amyloid immunoreactive deposits varying in size (less than 5-50 microns) and abundance. These results suggest that one mechanism of beta-amyloid formation may involve a disruption of the normal ratio of neuronal beta-APP isoform expression and support a direct relationship between increased expression of Kunitz inhibitor-bearing beta-APP isoforms and beta-amyloid deposition.

Alzheimer Disease↗
PubMed1991

Sequence and structural organization of the human gene encoding ciliary neurotrophic factor.

Ciliary neurotrophic factor (CNTF) is a potent polypeptide hormone whose actions appear to be restricted to the nervous system where it promotes survival, neurotransmitter synthesis and neurite outgrowth in certain neuronal populations. We have cloned the gene encoding human CNTF (hCNTF) and have characterized its structure and organization. The hCNTF gene appears to be a unique-copy gene with a simple genetic organization, since only a single intron interrupts the coding domain. The hCNTF gene is located on chromosome 11, as determined using human-hamster somatic cell hybrids. The CNTF protein is highly conserved in evolution. The amino acid (aa) sequences of rat and rabbit CNTF translated from cDNAs display approx. 85% homology with the deduced aa sequence encoding hCNTF.

Amino Acid Sequence↗
PubMed1991

Synthesis and characterization of the Kunitz protease-inhibitor domain of the beta-amyloid precursor protein.

To understand the pathological process by which amyloid is deposited in Alzheimer's disease, it is important to characterize the proteolytic processing events of the beta-amyloid precursor protein (beta-APP) from which the amyloid-forming fragment is excised. A potentially important component in beta-APP processing is the 57-amino acid (aa) Kunitz serine protease inhibitor (KPI) located within the extracellular domain of both the 751- and 770-aa isoforms of beta-APP. We have synthesized DNA encoding the 57-aa KPI domain as a necessary step in identifying the role of the protease inhibitor in beta-APP processing and amyloid formation. A bacterial secretion system directed by the alkaline phosphatase signal peptide of Escherichia coli linked to a synthetic gene encoding KPI was used to produce soluble, extracellular recombinant KPI (reKPI) protein. The reKPI protein was purified to homogeneity from bacterial supernatants and was biochemically and biologically characterized. Complete aa sequence analysis confirmed the fidelity of the reKPI, and fast-atom bombardment mass-spectral analysis was used to document that reKPI was of the predicted Mr. The reKPI is as active on a molar basis as the inhibitor-containing beta-APP when assayed for inhibition of trypsin activity. Together these data suggest that reKPI protein is properly folded and lacking in modified aa. Hence, this reKPI will be an important reagent in gaining a better understanding of the role of the KPI domain in beta-APP function and metabolism, as well as in the proteolytic events involved in beta-amyloid formation.

Alzheimer Disease↗
PubMed1991

Association of heparan sulfate proteoglycan with the neurofibrillary tangles of Alzheimer's disease.

The major intracytoplasmic lesion of Alzheimer's disease is the neurofibrillary tangle (NFT), which is primarily composed of paired helical filaments (PHFs). The mechanism responsible for the formation of PHFs, as well as their insolubility and apparent heterogeneity, is unknown. We found that basic fibroblast growth factor (bFGF) binds to heparinase-sensitive sites in NFTs. bFGF binding is due to a heparan sulfate proteoglycan (HSPG) immunocytochemically identified in NFTs. In the presence of polycations (e.g., Ca2+), HSPG will bind to free carboxyl groups in NFT proteins. HSPG binding may play a role in transforming normal soluble proteins into insoluble PHFs.

Aged↗
PubMed1990

Relation of neuronal APP-751/APP-695 mRNA ratio and neuritic plaque density in Alzheimer's disease.

An ongoing controversy concerns the cellular distribution of the differentially spliced forms of the amyloid protein precursor (APP) mRNAs and changes in prevalence of these transcripts during Alzheimer's disease. In situ hybridization on serial sections was used to prove that most hippocampal pyramidal neurons contain both APP-751 and APP-695 mRNA species. The APP-751/APP-695 mRNA ratio is generally increased during Alzheimer's disease, as shown by RNA gel blot analysis. Moreover, there was a strong linear relation between the increase in APP-751/APP-695 mRNA ratio in pyramidal neurons and the density of senile plaques within the hippocampus and entorhinal cortex. Thus, the increase in APP-751/APP-695 mRNA provides a molecular marker for regional variations in plaque density between individuals diagnosed with Alzheimer's disease by the commonly used composite criteria.

Alzheimer Disease↗
PubMed1990

Protease-specificity of Kunitz inhibitor domain of Alzheimer's disease amyloid protein precursor.

The putative inhibitor domain of Alzheimer's disease amyloid protein precursor was purified from E. coli containing a synthetic gene encoding the Kunitz domain. The purified protein (A4 inhibitor) inhibited the activity of trypsin, forming a 1:1 molar complex with the enzyme. It also strongly inhibited plasmin (Ki = 7.5 x 10(-11) M) from human serum and tryptase (Ki = 2.2 x 10(-10) M) from rat mast cells (tryptase M). In addition, it inhibited rat pancreatic trypsin, alpha-chymotrypsin and kallikrein and human serum kallikrein, but did not inhibit rat chymase, pancreatic elastase, alpha-thrombin, urokinase, papain or cathepsin B.

Amino Acid Sequence↗
PubMed1990

Fibroblast growth factor induces beta-amyloid precursor mRNA in glial but not neuronal cultured cells.

Treatment of PC12 and C6 cell cultures with recombinant basic fibroblast growth factor results in approximately a five to ten-fold stimulation of beta-amyloid precursor mRNA in the C6 astrocytoma cell line but only a slight induction of precursor mRNA in the PC-12 neuronal cell line. Stimulation of expression occurred at a hormone concentration of approximately 0.5 to 1 nM and was seen after 2 days. These results suggest that basic fibroblast growth factor may contribute to amyloidosis of Alzheimer's disease.

Alzheimer Disease↗
PubMed1990

Identification and characterization of C-terminal fragments of the beta-amyloid precursor produced in cell culture.

The mechanism of amyloid formation in Alzheimer's disease is unknown but appears to involve proteolytic processing of the amyloidogenic peptide from a larger precursor. When the C-terminus containing the amyloid-forming and cytoplasmic domains of the precursor was recombinantly expressed in cultured mammalian cells, a 16 kd protein accumulated which had a tendency to aggregate and form deposits. These deposits had physical characteristics resembling those of preamyloid. Recombinant expression of the full-length precursor was found to produce a similar, cell-associated 16 kd C-terminal fragment as well as a 12 kd fragment, neither of which formed detectable aggregates suggesting efficient catabolism of these fragments. Identification of these two naturally occurring metabolic products of the beta-amyloid precursor provides a system permitting the characterization of the proteolytic processing events of the amyloid precursor protein.

Alzheimer Disease↗
PubMed1990

Beta-amyloid precursor detected in human cerebral cortex.

1. Amyloid deposition is one of the pathologic hallmarks of Alzheimer's disease. Since the isolation of the beta-amyloid gene, which revealed that the amyloid forming 4 kD protein is part of a larger precursor, interest has focused on the process by which amyloid is generated and deposited. 2. The authors have developed an immunologic means of detecting amyloid precursor proteins in human brain. 3. The method involves the expression of human beta-amyloid precursor cDNA in a recombinant vaccinia virus, so that antibodies are produced against the precursor proteins in their native forms. 4. By using this expression system, the amyloid precursor immunogens incorporate post-translational modifications that normally occur in vivo; this cannot be achieved with small synthetic peptides. 5. Using antibodies to the 695 residue amyloid precursor, we have detected using Western blot analysis a protein of approximately 120 kD in samples of cerebral cortex from three subjects with Alzheimer's disease and one control subject. 6. Additional antibodies to other amyloid-related proteins have been developed. These are being used to assess the differential expression of the various amyloid precursors and subdomains in additional cases.

Adult↗