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A J Tenner

Publications and source records attributed to A J Tenner.

63 records · Page 4Linked to original sources
PubMed1981

Purification and radiolabeling of human C1q.

A new procedure for isolating human C1q from serum or plasma is described. The method, that is highly selective, rapid and involves minimal handling, yields fully active, immunoglobulin-free unaggregated C1q. Several different methods of radiolabeling C1q are compared. These include two methods selective for tyrosine residues, two that label lysine residues, and a method that labels sialic acid residues. The effect of each of the labeling procedures on C1q hemolytic activity was assessed. Also appraised for each method was the ability of the labeled molecules to bind to antibody sensitized cells and to interact with C1r and C1s to form C1. The distribution of each of the radiolabels among the three polypeptide chains of C1q and between the collagenous and globular regions of C1q was determined. Methods were identified that selectively labeled the globular portion of either the A or C polypeptide chain of the C1q molecule without loss of functional activity. Another of the methods labeled all three polypeptide chains relatively uniformly without significant loss of activity.

Carbon Radioisotopes↗
PubMed1980

Analysis of receptor-mediated C1q binding to human peripheral blood mononuclear cells.

The binding of C1q to human peripheral blood leukocytes has been investigated. Studies with fluorescein conjugated F(ab')2 anti-C1q show that few (0 to 4%) normal leukocytes isolated in the presence of EDTA have C1q on their surface. However, approximately 26% of the mononuclear cell population is able to bind added C1q. Quantitative binding studies using 125I-C1q show that the binding to mononuclear cells is specific, saturable, and reversible. Scatchard plot analyses indicate an approximate equilibrium constant of 1.2 times 10(7) M-1. C1q binding appears to be mediated via the collagenous portion of the molecule in that 1) type I collagen inhibits this binding; 2) C1 reconstituted from purified C1q, C1r, and C1s does not bind to mononuclear cells, whereas the same amount of free C1q binds avidly; and 3) C1q enhances the binding of aggregated IgG to mononuclear cells.

Binding Sites↗
PubMed1979

Lipid-saccharide intermediates and glycoprotein biosynthesis in a temperature-sensitive Chinese hamster cell mutant.

The characterization of a temperature-sensitive Chinese hamster cell mutant has been continued with the aim of localizing the apparent defect in glycoprotein synthesis (Tenner et al., '77). Although the mutation is lethal, a demonstration of the ability of the mutant cells to support proliferation of Mengo virus at the nonpermissive temperature indicates that the general metabolic processes of the cells remain intact at a time when glycoprotein synthesis is severely depressed. A quantitative study of protein synthesis on membrane-associated polysomes suggests that the synthesis of the polypeptide portion of the glycoproteins at 40.8 degrees C may be normal. The investigation of lipid-saccharide molecules which have been implicated in the formation and transfer of the oligosaccharide "core" to polypeptide acceptors shows that mutant cells at the nonpermissive temperature are capable of synthesizing these lipid saccharides normally, and that the pool of the dolichyl oligosaccharides is maintained at a constant level independent of the temperature. The rate of formation of the lipid-oligosaccharide, however, is reduced in intact mutant cells at the nonpermissive temperature. Further investigations show this decreased rate to be the result of an increased half life of the lipid-oligosaccharide at 40.8 degrees C. These data indicate that the temperature-sensitive step in glycoprotein biosynthesis is the transfer of the oligosaccharide core from the lipid-oligosaccharide intermediates to the nascent polypeptide chain. The data presented also provide evidence that the lipid-saccharide intermediates, previously described mainly in in vitro systems, are in fact involved in the glycosylation of a majority, if not all, of the mannose-containing glycoproteins in intact, growing hamster cells.

Animals↗
PubMedDate not supplied

Decreased levels of C1q in cerebrospinal fluid of living Alzheimer patients correlate with disease state.

Recent reports that complement proteins comprising the classical pathway are associated with senile plaques suggest that activation of the classical complement cascade in Alzheimer's disease tissue results in bystander cell lysis and may contribute to AD neuropathology. Analysis of cerebrospinal fluid may prove to be a useful means of detecting changes in immunological activity in the brain. We use an enzyme-linked immunosorbent assay to measure levels of C1q, a subunit of the classical complement cascade, in the CSF of patients clinically diagnosed with possible or probable AD. Significantly lower levels of C1q were detected in the CSF of the Alzheimer group as compared to control CSF [AD: mu = 268 ng/ml, SD = 84; non-AD: mu = 340 ng/ml, SD = 76; F(1, 44) = 5.84, p = 0.02]. Diminished performance on global measures of mental status such as the Mini-Mental State Exam (R = 0.45; p = 0.0072) and Blessed's Information, Memory, and Concentration test (R = 0.42; p = 0.0138) showed high correlations with decreased C1q levels. More specific measures of cognitive function, such as word recall (R = 0.42; p = 0.012), word recognition (R = 0.52; p = 0.0017) and delayed recall (R = 0.45; p = 0.0062) memory tasks also correlated strongly with decreased C1q levels.

Adult↗
PubMedDate not supplied

beta-Amyloid converts an acute phase injury response to chronic injury responses.

As the brain ages, amyloid deposits accumulate and, as these deposits condense into a beta-sheet conformation, they contribute to the organization of cellular responses and maintain a chronic level of stimulation and injury. Furthermore, accompanying reactions can lead to the production of additional beta-amyloid, the build up of additional fibrillar beta-amyloid, and prolongation of the response. As it accumulates, beta-amyloid appears to develop properties that drive many signal transduction processes in the classic injury cascade and also activate complement, which results in an amplified beta-amyloid AD cascade. In this way several mechanisms, although apparently independent, proceed in parallel, reinforce each other, and perpetuate pathology and structural damage to the brain. Specifically, we suggest that via the activation of complement, initiation, and perpetuation of other cascades, and its own direct toxic actions, beta-amyloid converts an acute response to injury into a chronic damaging inflammatory reaction thereby contributing to neuronal dysfunction and degeneration.

Acute-Phase Reaction↗
PubMedDate not supplied

Complement in Alzheimer's disease: opportunities for modulating protective and pathogenic events.

The complement system is a critical element of the innate immune system recognizing and killing, or targeting for destruction, otherwise pathogenic organisms. In addition to triggering the generation of a membranolytic complex, complement proteins interact with cell surface receptors to promote a local inflammatory response that contributes to the protection and healing of the host. Compelling evidence has been reported that in Alzheimer's Disease complement activation occurs in the brain, and that this contributes to the development of a local inflammatory state that is correlated with cognitive dysfunction. However, recent data suggest that at least some of the complement components have the ability to contribute to neuroprotective pathways. Thus, it is the balance of these seemingly competing events that influences the ultimate state of neuronal function. Knowledge of the unique molecular interactions that occur in the development of Alzheimer's Disease, the functional consequences of those interactions, and the proportional contribution of each element to this disorder, should facilitate the design of effective therapeutic strategies for this disease.

Alzheimer Disease↗
PubMedDate not supplied

Molecular and cellular characterization of the membrane attack complex, C5b-9, in Alzheimer's disease.

The membrane attack complex, C5b-9, is of considerable importance in many inflammatory reactions. It is the terminal, cytolytic component of both classical and alternative pathway activation, and its presence presupposes other potentially destructive complement constituents, including anaphylotoxins and opsonins. We have characterized C5b-9 and its C9 constituent in the Alzheimer's disease (AD) and nondemented elderly (ND) brain using immunohistochemistry at the light and electron microscopic levels, Western blot analysis, and the reverse transcriptase polymerase chain reaction. We have also conducted in vitro ELISA assays of amyloid beta-peptide-stimulated SC5b-9 production. C5b-9 is abundantly present in Alzheimer's disease cortex, associated with neurofibrillary tangle containing neurons, dystrophic neurites within neuritic plaques, and neuropil threads, but is weakly detected, if at all, in nondemented elderly cortex under the same conditions. Staining of Alzheimer's disease sections is abolished both by deletion of primary antibody or preabsorption with purified SC5b-9.

Alzheimer Disease↗
PubMedDate not supplied

The mouse C1q A-chain sequence alters beta-amyloid-induced complement activation.

In transgenic models of Alzheimer's disease (AD) neuronal loss has not been widely observed. The loss of neurons in AD may be due to chronic activation of complement (C') by beta-amyloid (A beta). A beta has been shown to activate C' by binding to a site on the C1q A-chain. The mouse A-chain sequence differs significantly from human, and a peptide based on the mouse A-chain sequence was ineffective at blocking activation of C' by A beta in contrast to the inhibition seen with the human peptide. Comparison of mouse and human serum showed that human C' was activated more effectively by A beta than was mouse C'. Therefore, additional genetic manipulations may be necessary to replicate in the murine model the inflammation and neurodegeneration that occur in AD.

Alzheimer Disease↗