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Biomedical subjects

B Cordell

Publications and source records attributed to B Cordell.

At least 37 records · Page 2Linked to original sources
PubMed1997

Empowerment as a source of healing: redefining the art of nursing management.

Empowerment amounts to a social process of recognizing, promoting and enhancing staff nurse abilities to meet self needs, solve their own problems and mobilize the necessary resources to gain mastery over their own professional lives. Healing, to be made whole, is a process of getting in touch with that which is impeding our realization of wholeness. Empowerment as a source of organizational healing conveys the message that in order to realize wholeness, nurses are dependent upon personal and organizational resources. As nurses learn multiple ways to interact with the work environment, they find the path to a wholeness that incorporates physical, emotional, intellectual, and spiritual aspects of themselves. As the value of wholeness is realized individually, interactions with the environment spontaneously manifest these attributes and the message permeates the nursing community. As the nursing community is empowered, it is increasingly able to empower the individual. This expanding energy can result in a synergistic pattern that brings phenomena together, and interrelates them, creating a new and greater whole from the disparate, seemingly conflicting parts. When nurses as individuals and groups are able and willing (empowered) to invest energy to that which impacts their lives so that they can move toward wholeness (heal), positive energy exponentially intensifies and permeates the environment to envelop all.

Decision Making, Organizational↗
PubMed1996

Processing of beta-amyloid precursor protein by cathepsin D.

The events leading to the formation of beta-amyloid (betaA4) from its precursor (betaAPP) involve proteolytic cleavages that produce the amino and carboxyl termini of betaA4. The enzyme activities responsible for these cleavages have been termed beta- and gamma-secretase, respectively, although these protease(s) have not been identified. Since betaA4 is known to possess heterogeneity at both the amino and carboxyl termini, beta- and gamma-secretases may actually be a collection of proteolytic activities or perhaps a single proteolytic enzyme with broad amino acid specificity. We investigated the role of cathepsin D in the processing of betaAPP since this enzyme has been widely proposed as a gamma-secretase candidate. Treatment of a synthetic peptide that spans the gamma-secretase site of betaAPP with human cathepsin D resulted in the cleavage of this substrate at Ala42-Thr43. A sensitive liquid chromatography/mass spectrometry technique was also developed to further investigate the ability of cathepsin D to process longer recombinant betaAPP substrates (156 and 100 amino acids of betaAPP carboxyl terminus) in vitro. The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. No cleavages were observed at putative gamma-secretase sites: Val40-Ile41 or Ala42-Thr43, suggesting that cathepsin D is not gamma-secretase as defined by these betaA4 termini. Under conditions where the betaAPP156 substrate was first denatured prior to cathepsin D digestion, two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.

Amino Acid Sequence↗
PubMed1996

Beta-amyloid precursor protein. Location of transmembrane domain and specificity of gamma-secretase cleavage.

The formation of beta-amyloid by processing of its precursor protein is a characteristic of Alzheimer's disease. Two proteolytic cleavages produce the amino and carboxyl termini of beta-amyloid, with the latter cleavage site located within the transmembrane domain. Using DNA mutagenesis, we investigated the membrane position and sequence requirements for carboxyl-terminal processing of the beta-amyloid domain. Substitution of negatively charged residues across positions 40-46 of the beta-amyloid domain precluded both beta-amyloid formation and precursor maturation associated with secretory protein transport. In contrast, identical substitutions from positions 48-50 had no adverse effects. Since charged residues typically prevent protein membrane insertion, these data define the membrane boundary to position 46/47, a location allowing greater access to carboxyl-terminal processing of beta-amyloid, possibly without membrane destruction. Deletions within the carboxyl-terminal domain, including 4 residues spanning positions 39-42 of beta-amyloid, resulted in formation of the beta-amyloid peptide. Substituting residues 38-47 or 39-56 of the beta-amyloid domain in the precursor with a transmembrane sequence from another protein yielded a approximately 4-kDa beta-amyloid peptide, reflecting a loose residue specificity for carboxyl-terminal processing to beta-amyloid.

Amino Acid Sequence↗
PubMed1996

Beta-amyloid peptide secretion by a microglial cell line is induced by beta-amyloid-(25-35) and lipopolysaccharide.

beta-Amyloid protein (betaAP) deposition is a neuropathologic hallmark of Alzheimer's disease (AD). Yet, the source of cerebral betaAP in AD is controversial. We examined the production of betaAP by the BV-2 immortalized microglial cell line using a sensitive enzyme immunoassay. Constitutive production of betaAP was detected in conditioned media from unstimulated BV-2 cells. Further, production of betaAP was induced by treatment of cultures by lipopolysaccharide (LPS) or betaAP-(25-35) and was inhibited by the calpain protease inhibitor MDL 28170. Treatment of BV-2 cells with LPS or betaAP-(25-35) did not affect cell-associated beta-amyloid precursor protein levels. These findings suggest that microglia may be an important source of betaAP in AD, and that microglial production of betaAP may be augmented by proinflammatory stimuli or by betaAP itself.

Alzheimer Disease↗
PubMed1996

Genetically Engineered Animal Models of Alzheimer's Disease

The application of transgenic research has proven to be a powerful and popular tool for investigating the contribution of specific genes known or suspected to be involved in the pathology of Alzheimer's disease. Many different experimental approaches have been pursued in an effort to mimic one or more of the numerous and diverse features characterizing Alzheimer's disease. Results have been variable but not without successes. Some of the cardinal hallmarks of this disorder have been recapitulated through the manipulation of a single gene, providing information on the interrelationship between several pathological events. Also, through the generation of such transgenic animals, potential models are being established for this disease that will be valuable for development of intervention strategies.

Journal Article↗
PubMed1996

P3 beta-amyloid peptide has a unique and potentially pathogenic immunohistochemical profile in Alzheimer's disease brain.

The presence of beta-amyloid in brain tissue is characteristic of Alzheimer's disease (AD). A naturally occurring derivative of the beta-amyloid peptide, p3, possesses all of the structural determinants required for fibril assembly and neurotoxicity. p3-specific antibodies were used to examine the distribution of this peptide in brain. p3 reactivity was absent or sparse in aged non-AD brains but was prevalent in selected areas of AD brain in diffuse deposits and in a subset of dystrophic neurites. p3-reactive dystrophic neurites were found both independent in the neuropil and associated with plaques. Little or no reactivity was observed to amyloid cores in classical plaques or to amyloid in the cerebral vasculature. The exclusive appearance of p3 reactivity in AD brain plus the selective localization of p3 reactivity to abnormal structures in the temporal lobe limbic system suggests that p3 may be a contributing factor to AD pathology.

Alzheimer Disease↗
PubMed1996

Antibodies to presenilin proteins detect neurofibrillary tangles in Alzheimer's disease.

Mutations in the presenilin (PS)-1 and PS-2 genes have been shown to be linked with the development of Alzheimer's disease (AD). We examined Alzheimer's brain tissue by immunohistochemistry using a set of antibodies raised to sequences shared between PS-1 and PS-2 proteins. These antibodies reacted exclusively with a subset of neurofibrillary tangles and not with neuropil threads or dystrophic neurites. Detection of the presenilin epitope in neurofibrillary tangles was observed in sporadic Alzheimer's disease brain samples and in samples from individuals carrying PS-1 and PS-2 mutations with no qualitative difference. These data indicate that both wild-type and mutant PS proteins are involved in a common pathogenic pathway in AD.

Alzheimer Disease↗
PubMed1995

Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human beta-amyloid precursor protein.

The beta-amyloid precursor protein (beta-APP), from which the beta-A4 peptide is derived, is considered to be central to the pathogenesis of Alzheimer disease (AD). Transgenic mice expressing the 751-amino acid isoform of human beta-APP (beta-APP751) have been shown to develop early AD-like histopathology with diffuse deposits of beta-A4 and aberrant tau protein expression in the brain, particularly in the hippocampus, cortex, and amygdala. We now report that beta-APP751 transgenic mice exhibit age-dependent deficits in spatial learning in a water-maze task and in spontaneous alternation in a Y maze. These deficits were mild or absent in 6-month-old transgenic mice but were severe in 12-month-old transgenic mice compared to age-matched wild-type control mice. No other behavioral abnormalities were observed. These mice therefore model the progressive learning and memory impairment that is a cardinal feature of AD. These results provide evidence for a relationship between abnormal expression of beta-APP and cognitive impairments.

Aging↗
PubMed1995

Early Alzheimer disease-like histopathology increases in frequency with age in mice transgenic for beta-APP751.

beta-Amyloid deposition and neurofibrillary tangle formation are two histopathological features of Alzheimer disease. We have previously reported that beta-amyloid immunoreactive deposits form in the brains of transgenic mice programmed for neuronal expression of the 751-amino acid isoform of human beta-amyloid precursor protein (beta-APP751) and now describe that these animals also display Alz50 intraneuronal immunoreactivity similar to that seen in early Alzheimer disease. This suggests that abnormal beta-APP expression and/or beta-amyloid deposition promotes pathogenic alterations in tau protein. The frequency of both beta-amyloid deposition and Alz50-positive neurons was twice as prevalent in brains from old (22 months) as compared to young (2-3 months) beta-APP751 transgenic mice. This increase in histopathology with age in beta-APP751 transgenic mice parallels the time-dependent progression seen in the human disease.

Alzheimer Disease↗
PubMed1995

beta-Amyloid peptide produced in vitro is degraded by proteinases released by cultured cells.

The primary histopathological feature of Alzheimer's disease is the accumulation of beta-amyloid in the brains of afflicted individuals. This peptide has been shown to be produced and liberated both in vitro and in vivo by normal physiological processes. The mechanism by which beta-amyloid is formed, as well as that by which it may be cleared, are events likely to impact on the development and progression of this disease. Thus, the fate of beta-amyloid peptides secreted by cultured mammalian cells was investigated. It was found that levels of the soluble peptide are reduced over time due to the activity of multiple types of proteinases including those from the metallo, aspartyl, and thiol classes. Inhibitors to each class of proteinase can only partially block beta-amyloid degradation, but, if used in combination, they can fully prevent its catabolism. The Kunitz serine proteinase inhibitor domain, present on two beta-amyloid precursor protein isoforms, was found to be an effective inhibitor of beta-amyloid peptide degradation. These data indicate that modulations in expression of secreted proteinases and/or beta-amyloid precursor isoforms may influence levels of beta-amyloid.

Amyloid beta-Peptides↗
PubMed1995

Genetically engineered animal models of human neurodegenerative diseases.

The influence of a single gene, engineered to be normally or abnormally expressed, can be evaluated in vivo through the development of transgenic animals. Application of this approach in the study of human neurological problems is contributing to an increased understanding of the pathogenic components operative in a variety of disorders. These include Alzheimer's disease, prion encephalopathies, motor neuron disease such as amyotrophic lateral sclerosis, and fragile X syndrome, as well as a number of viral-mediated neurological disorders. These transgenic animals can also serve as models to investigate the possible involvement of additional genetic and environmental factors on the disease state. Moreover, transgenic animals can be used in the development of intervention strategies. The application of this powerful and increasingly popular tool to investigate neurodegenerative disorders is reviewed.

Amyotrophic Lateral Sclerosis↗
PubMed1995

Inhibition of beta-amyloid formation identifies proteolytic precursors and subcellular site of catabolism.

Cerebral deposition of beta-amyloid protein is a pathological feature central to Alzheimer's disease. Production of beta-amyloid by proteolytic processing of the beta-amyloid precursor protein (beta APP) is a critical initial step in beta-amyloidogenesis. We use an inhibitor of beta APP processing to block beta-amyloid peptide formation. Application of the inhibitor to cultured cells results in an accumulation of proteolytic intermediates of beta APP, enabling a precursor-product relationship between beta APP carboxy-terminal fragments and beta-amyloid peptides to be demonstrated directly. In the presence of inhibitor, these amyloidogenic carboxy-terminal fragments can be degraded to nonamyloidogenic products. The catabolism of beta APP carboxy-terminal intermediates and the formation of beta-amyloid peptides are likely to involve an early endosomal compartment as the subcellular site of processing.

Alzheimer Disease↗
PubMed1994

Increased amyloid production from aberrant beta-amyloid precursor proteins.

The 4-kDa beta-amyloid protein that forms fibrillar deposits in Alzheimer's diseased brains is derived from a large precursor, the beta-amyloid precursor protein (beta-APP). Recently, it has been reported that beta-amyloid is normally produced and secreted by cultured mammalian cells. In our studies involving recombinant expression of beta-APP, increased yields of beta-amyloid were associated with expression of aberrant beta-APP molecules. Deletion mutations within the beta-amyloid domain, incorrect beta-APP isoform expression in fibroblasts or neuronal cells, or excess amounts of beta-APP all led to increases in beta-amyloid production. Aberrant beta-APP appears to be diverted from the secretory pathway and then degraded to beta-amyloid.

Amyloid beta-Peptides↗
PubMed1994

Secretion of beta-amyloid precursor protein involves multiple cleavage sites.

A major histopathological feature of Alzheimer's disease is deposits of a approximately 4-kDa beta-amyloid peptide derived by proteolytic processing from a precursor, the beta-amyloid precursor protein (beta-APP). Proteolytic cleavage of beta-APP within the approximately 4-kDa beta-amyloid domain permits the secretion of the amino-terminal portion of beta-APP while concomitantly producing a membrane bound approximately 9-kDa carboxyl-terminal fragment. We have characterized the proteolytic cleavage site for beta-APP secretion by amino acid sequence analysis of the approximately 9-kDa beta-APP carboxyl-terminal cleavage product produced by recombinant and native expression systems. Recombinant beta-APP was generated by a vaccinia virus expression system in CV-1 monkey fibroblasts; endogenous beta-APP was obtained using a fibroblast line derived from an individual with Down's syndrome. The sequences of both unlabeled and metabolically radiolabeled approximately 9-kDa fragment from CV-1 cells reveal that the major (60%) secretory cleavage site is after Lys16 of the beta-amyloid domain as reported previously; however, an additional cleavage site is seen after Phe19 (40%). Radiosequence analysis of the carboxyl-terminal fragment purified from Down's syndrome fibroblasts indicates cleavage sites after Phe19, Glu22, and Gly25 and not after Lys16. CV-1 cells expressing beta-APP mutants lacking 4 and 6 amino acids adjacent to Lys16 yielded approximately 9-kDa fragments with two identical cleavage sites, neither of which occurred after the retained Lys16 but were after Glu11 and His13. These data suggest that secretion of beta-APP involves multiple proteinases and that the composition of these proteinases may vary within different cell backgrounds.

Amino Acid Sequence↗
PubMed1994

Transgenic mouse brain histopathology resembles early Alzheimer's disease.

Transgenic mice expressing the 751-amino acid form of the human amyloid precursor protein develop extracellular beta-amyloid protein (A beta)-immunoreactive deposits that increase in frequency with age. Here we show that the appearance and histological profile of deposits in the transgenic mice closely resemble those of preamyloid deposits in the brains of young adults with Down's syndrome, who presumably have the pathology of early-stage Alzheimer's disease. Specific monoclonal antibodies reveal that material in the deposits has the free carboxyl terminus of A beta 1-42, and that the deposits contain material which, by immunohistochemical analysis, apparently originates from the human beta-amyloid precursor protein (beta PP) transgene. In rare cases, the transgenic mouse brains contain several different histopathological characteristics of Alzheimer lesions. These features include dense A beta immunoreactivity which co-localizes with gliosis and with Alz50-immunoreactive structures resembling swollen boutons of dystrophic neurites. These observations demonstrate that the murine brain is capable of reproducing several typical features of Alzheimer histopathology.

Alzheimer Disease↗