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  • 1
    Electronic Resource
    Electronic Resource
    Molecular Cloning, Expression, and Chromosomal Localization of a Human Brain-Specific Na+-Dependent Inorganic Phosphate Cotransporter (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 66 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: We describe the molecular cloning of a cDNA encoding a human brain Na+-dependent inorganic phosphate (Pi) cotransporter (hBNPI). The nucleotide and deduced amino acid sequences of hBNPI reveal a protein of 560 amino acids with six to eight putative transmembrane segments. hBNPI shares a high degree of homology with other Na+-dependent inorganic Pi cotransporters, including those found in rat brain and human and rabbit kidney. Expression of hBNPI in COS-1 cells results in Na+-dependent Pi uptake. Northern blot analysis demonstrates that hBNPI mRNA is expressed predominantly in brain and most abundantly in neuron-enriched regions such as the amygdala and hippocampus. Moderate levels of expression are also observed in glia-enriched areas such as the corpus callosum, and low levels are observed in the substantia nigra, subthalamic nuclei, and thalamus. In situ hybridization histochemistry reveals relatively high levels of hBNPI mRNA in pyramidal neurons of the cerebral cortex and hippocampus and in granule neurons of dentate gyrus. The level of hBNPI mRNA is quite low in fetal compared with adult human brain, suggesting developmental regulation of hBNPI gene expression. Southern analyses of nine eukaryotic genomic DNAs probed under stringent conditions with hBNPI cDNA revealed that the hBNPI gene is highly conserved during vertebrate evolution and that each gene is most likely present as a single copy. Using fluorescent in situ hybridization, we localized hBNPI to the long arm of chromosome 19 (19q13) in close proximity to the late-onset familial Alzheimer's disease locus.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.66062227.x
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  • 2
    Electronic Resource
    Electronic Resource
    α2-Macroglobulin Attenuates β-Amyloid Peptide 1–40 Fibril Formation and Associated Neurotoxicity of Cultured Fetal Rat Cortical Neurons (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 70 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: β-Amyloid peptides (Aβ) are deposited in an aggregated fibrillar form in both diffuse and senile plaques in the brains of patients with Alzheimer's disease. The neurotoxicity of Aβ in cultured neurons is dependent on its aggregation state, but the factors contributing to aggregation and fibril formation are poorly understood. In the present study, we investigated whether α2-macroglobulin (α2M), a protein present in neuritic plaques and elevated in Alzheimer's disease brain, is a potential regulatory factor for Aβ fibril formation. Previous studies in our laboratory have shown that α2M is an Aβ binding protein. We now report that, in contrast to another plaque-associated protein, α1-antichymotrypsin, α2M coincubated with Aβ significantly reduces aggregation and fibril formation in vitro. Additionally, cultured fetal rat cortical neurons are less vulnerable to the toxic actions of aged Aβ following pretreatment with α2M. We postulate that α2M is able to maintain Aβ in a soluble state, preventing fibril formation and associated neurotoxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.70031182.x
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  • 3
    Electronic Resource
    Electronic Resource
    α2-Macroglobulin as a β-Amyloid Peptide-Binding Plasma Protein (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 69 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The β-amyloid peptide (Aβ) is a normal proteolytic processing product of the amyloid precursor protein, which is constitutively expressed by many, if not most, cells. For reasons that are still unclear, Aβ is deposited in an aggregated fibrillar form in both diffuse and senile plaques in the brains of patients with Alzheimer's disease (AD). The factor(s) responsible for the clearance of soluble Aβ from biological fluids or tissues are poorly understood. We now report that human α2-macroglobulin (α2M), a major circulating endoproteinase inhibitor, which has recently been shown to be present in senile plaques in AD, binds 125I-Aβ(1–42) with high affinity (apparent dissociation constant of 3.8 × 10−10M). Approximately 1 mol of Aβ is bound per mole of α2M. Both native and methylamine-activated α2M bind 125I-Aβ(1–42). The binding of 125I-Aβ(1–42) to α2M is enhanced by micromolar concentrations of Zn2+ (but not Ca2+) and is inhibited by noniodinated Aβ(1–42) and Aβ(1–40) but not by the reverse peptide Aβ(40-1) or the cytokines interleukin 1β or interleukin 2. α1-Antichymotrypsin, another plaque-associated protein, inhibits both the binding of 125I-Aβ(1–42) to α2M as well as the degradation of 125I-Aβ(1–42) by proteinase-activated α2M. Moreover, the binding of 125I-Aβ(1–42) to α2M protects the peptide from proteolysis by exogenous trypsin. These data suggest that α2M may function as a carrier protein for Aβ and could serve to either facilitate or impede clearance of Aβ from tissues such as the brain.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.69010299.x
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  • 4
    Electronic Resource
    Electronic Resource
    Sodium Salicylate and 17β-Estradiol Attenuate Nuclear Transcription Factor NF-κB Translocation in Cultured Rat Astroglial Cultures Following Exposure to Amyloid Aβ1-40 and Lipoplysaccharides (1999)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 73 (1999), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract : In recent years inflammatory mechanisms have become increasingly appreciated as important steps in the Alzheimer's pathogenic pathway. There is accumulating evidence that amyloid β-peptide (Aβ), the peptide product of the cleavage of amyloid precursor protein, may promote or exacerbate local inflammation by stimulating glial cells to release immune mediators. In addition, clinical studies using nonsteroidal antiinflammatory drugs have found a reduced risk for Alzheimer's disease with their use. Here we show that the neurotoxic Aβ, a major plaque component, and lipopolysaccharides (LPS), an immune reaction-triggering portion of bacterial membranes, are both potent activators of the nuclear transcription factor NF-κB in primary rat astroglial cells. The activation was found to be concentration- and time-dependent and could be attenuated in the presence of NF-κB decoy nucleotides. The pretreatment by either 17β-estradiol (1-10 μg) or sodium salicylate (3-30 mM) reduced the Aβ (LPS)-induced activation of NF-κB by 48 (50%) and 60% (50%) of activated levels, respectively. In addition, 17β-estradiol (10 μM) and sodium salicylate (10 mM) were able to attenuate the increase in interleukin-1β levels following exposure to 25 μM Aβ. Our data suggest that the aberrant gene expression is at least in part due to Aβ-induced activation of NF-κB, a potent immediatearly transcriptional regulator of numerous proinflammatory genes ; this event takes place in astroglial cells. The results of our experiments provide a further understanding of the effects of estrogen and aspirin on astroglial cells exposed to Aβ and LPS.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0731453.x
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  • 5
    Electronic Resource
    Electronic Resource
    Minocycline blocks bilirubin neurotoxicity and prevents hyperbilirubinemia-induced cerebellar hypoplasia in the Gunn rat (2005)
    Oxford, UK : Blackwell Science Ltd
    European journal of neuroscience 22 (2005), S. 0 
    Details
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Encephalopathy induced by hyperbilirubinemia in infants has been described in the medical literature for over a century but neither the cellular nor molecular mechanisms underlying bilirubin neurotoxicity are well understood. In this study, we have demonstrated that minocycline potently protects primary cultured rat cerebellar granule neurons against bilirubin neurotoxicity (IC50 ≈ 2 µm) and almost completely blocks cerebellar hypoplasia and the profound loss of Purkinje and granule neurons observed in homozygous Gunn rats, a genetic model of hyperbilirubinemia-induced neurotoxicity. Minocycline-treated newborn Gunn rats had nearly equivalent numbers of viable Purkinje and granule neurons in the cerebellum as did control animals. Moreover, minocycline inhibits the bilirubin-induced phosphorylation of p38 mitogen-activated protein kinase both in vivo as well as in vitro. Taken together our data demonstrate that minocycline is able to greatly reduce bilirubin-induced neurotoxicity and suggest that minocycline's neuroprotective effects may be due in part to an inhibition of p38 mitogen-activated protein kinase activity. Our findings may lead to novel approaches for treating bilirubin-induced encephalopathy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1460-9568.2005.04182.x
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  • 6
    Electronic Resource
    Electronic Resource
    Deleterious effects of minocycline in animal models of Parkinson's disease and Huntington's disease (2004)
    Oxford, UK : Blackwell Science Ltd
    European journal of neuroscience 19 (2004), S. 0 
    Details
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Minocycline has been shown to exert anti-inflammatory effects underlying its putative neuroprotective properties in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease and in the R6/2 mouse model of Huntington's disease (HD). However, contradictory results have recently been reported. We report deleterious effects of minocycline in two phenotypic (toxic) models of Parkinson's disease and HD in monkey and mouse. Of seven MPTP-intoxicated female cynomolgus monkeys (0.2 mg/kg, i.v. until day 15), three received minocycline (200 mg b.i.d.). While placebo-MPTP-treated animals displayed mild parkinsonism at day 15, the minocycline/MPTP-treated animals tended to be more affected (P = 0.057) and showed a greater loss of putaminal dopaminergic nerve endings (P 〈 0.0001). In the 3-nitropropionic acid (3-NP) mouse model of HD, minocycline (45 mg/kg i.p.) was administered 30 min before each i.p. injection of 3-NP (b.i.d., cumulated dose, 360 mg/kg in 5 days). Mice receiving minocycline exhibited a worsening of the mean motor score with a slower recovery slope, more impaired general activity and significantly deteriorated performances on the rotarod, pole test and beam-traversing tasks. The histopathological outcome demonstrated that minocycline-treated mice presented significantly more severe neuronal cell loss in the dorsal striatum. The effect of minocycline vs. 3-NP was also investigated on hippocampal and cortical cell cultures. minocycline blocked 3-NP-induced neurotoxicity at certain doses (1 mm cortical neurons) but not at higher doses (10 mm). Thus, minocycline may have variable and even deleterious effects in different species and models according to the mode of administration and dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.0953-816X.2004.03372.x
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  • 7
    Electronic Resource
    Electronic Resource
    Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition (1997)
    [s.l.] : Nature Publishing Group
    Nature genetics 17 (1997), S. 263-264 
    Details
    ISSN: 1546-1718
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] APOLIPOPROTEIN E (APOE) appears to play an important role in the pathogenesis of Alzheimer's disease (AD), as the relative risk of developing late-onset senile dementia of the AD type is increased in individuals who inherit an APOEε4 allele1. In humans, APOE is a single gene located on ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/ng1197-263
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