Neuroscience
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Apolipoprotein E (apoE) alters the pathophysiology of Alzheimer's disease, but its mechanism is not fully understood. We examined the effects of recombinant human apoE3 and apoE4 on the neuronal calcium response to N-methyl-D-aspartate (NMDA), and compared them to their toxicity. ApoE4 (100 nM) significantly increased the resting calcium (by 70%) and the calcium response to NMDA (by 185%), whereas similar changes were not obtained in apoE3-treated neurons. ⋯ Both the receptor-associated protein, which inhibits interaction of apoE with members of the LDL receptor family, including the low-density lipoprotein receptor-related protein (LRP), and activated alpha2-macroglobulin, another LRP ligand, prevented apoE4-induced enhancement of the calcium response to NMDA, resting calcium levels, and neurotoxicity. A tandem apoE peptide (100 nM) containing only the receptor binding region residues also eliminated the enhanced calcium signaling and neurotoxicity by apoE4. Taken together, our data demonstrate that differential effects of apoE3 and apoE4 on the calcium signaling in neurons correlate with their effect on neurotoxicity, which are secondary to receptor binding.
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Acid-base transporters, such as the sodium-hydrogen exchangers (NHEs) and bicarbonate-dependent transporters, play an important role in the regulation of intracellular pH (pH(i)) in the CNS. Previous studies from our laboratory have shown that the absence of the major NHE isoform 1 (NHE1) reduced the steady-state pH(i) and recovery rate from an acid load in the hippocampal neurons not only in HEPES but also in HCO(3)(-) solutions (Yao et al., 1999). The purpose of the current study was to determine whether the NHE1 null mutation affects the expression of pH-regulatory transporters in the mouse CNS. ⋯ An increase in acid extruders (e.g. NHE3) and a decrease in acid loaders (e.g. AE3) suggest that there are some compensatory mechanisms that occur in NHE1 null mutant mice.
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Comparative Study
Microglial cell death induced by a low concentration of polyamines.
Pathological activation of microglia, which reside quiescently in physiological CNS, contributes various neurodegenerative diseases. Endogenous polyamines, spermidine (SPD) and spermine (SPM) are known to be activators of cell proliferation and differentiation. We examined the effect of polyamines on microglial activation in culture. ⋯ Fragmented DNA in the cytosol increased dose dependently with SPM; EC(50) was less than 10 microM. Furthermore, most of the cells after 24 h incubation with 10 microM SPD and SPM were positive for terminal deoxyribonucleotidyl transferase-mediated dUTP-biotin nick end labeling. These results suggest that microglial cell death is induced by a low concentration of polyamines via an apoptotic process rather than necrotic one.
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Neurotrophic factors direct axonal growth toward the target tissue by a concentration gradient, which is mediated through different tyrosine kinase cell surface receptors. In this study, well-defined concentration gradients of neurotrophic factors (NFs) allowed us to study the synergistic effect of different NFs (e.g. nerve growth factor [NGF], neurotrophin-3 [NT-3] and brain-derived neurotrophic factor [BDNF]) for axonal guidance of embryonic lumbar dorsal root ganglion cells (DRGs). ⋯ Interestingly, the combined concentration gradients of NGF and BDNF did not show any significant synergism at the concentration gradients studied. The synergism observed between NGF and NT-3 indicates that axons may be guided over a 12.5 mm distance, which is significantly greater than that of 7.5 mm calculated by us for NGF alone or that of 2 mm observed by others.
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Comparative Study
Growth hormone secretagogue receptors in rat and human gastrointestinal tract and the effects of ghrelin.
The peptide hormone ghrelin is known to be present within stomach and, to a lesser extent, elsewhere in gut. Although reports suggest that gastric function may be modulated by ghrelin acting via the vagus nerve, the gastrointestinal distribution and functions of its receptor, the growth hormone secretagogue receptor (GHS-R), are not clear and may show signs of species-dependency. This study sought to determine the cellular localisation and distribution of GHS-R-immunoreactivity (-Ir) using immunofluorescent histochemistry and explore the function of ghrelin in both human and rat isolated gastric and/or colonic circular muscle preparations in which nerve-mediated responses were evoked by electrical field stimulation. ⋯ When examined under similar conditions, in both rat distal colon (n=4-6, P>0.05 each) and human ascending (n=3) and sigmoid (n=1) colon, these concentrations of ghrelin were without effect (P>0.05 each). The data suggest that ghrelin has the potential to profoundly affect gastrointestinal functions in both species and at least one of these functions is to exert a gastric prokinetic activity. Moreover, we suggest that this activity of ghrelin is mediated via the enteric nervous system, in addition to known vagus nerve-dependent mechanisms.