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  • 1
    Electronic Resource
    Electronic Resource
    Plaque-associated disruption of CSF and plasma amyloid-β (Aβ) equilibrium in a mouse model of Alzheimer's disease (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 81 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: To better understand amyloid-β (Aβ) metabolism in vivo, we assessed the concentration of Aβ in the CSF and plasma of APPV717F (PDAPP) transgenic mice, a model that develops age-dependent Alzheimer's disease (AD)-like pathology. In 3-month-old mice, prior to the development of Aβ deposition in the brain, there was a highly significant correlation between Aβ levels in CSF and plasma. In 9-month-old-mice, an age at which some but not all mice have developed Aβ deposition, there was also a significant correlation between CSF and plasma Aβ; however, the correlation was not as strong as that present in young mice. In further exploring CSF and plasma Aβ levels in 9-month-old mice, levels of CSF Aβ were found to correlate highly with Aβ burden. Analysis of the CSF : plasma Aβ ratio revealed a selective two-fold increase in plaque versus non-plaque bearing mice, strongly suggesting a plaque-mediated sequestration of soluble Aβ in brain. Interestingly, in 9-month-old mice, a significant correlation between CNS and plasma Aβ was limited to mice lacking Aβ deposition. These findings suggest that there is a dynamic equilibrium between CNS and plasma Aβ, and that plaques create a new equilibrium because soluble CNS Aβ not only enters the plasma but also deposits onto amyloid plaques in the CNS.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.00889.x
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  • 2
    Electronic Resource
    Electronic Resource
    Involvement of a Caspase-3-Like Cysteine Protease in 1-Methyl-4-Phenylpyridinium-Mediated Apoptosis of Cultured Cerebellar Granule Neurons (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: Exposure of various neuronal cells or cell lines to high concentrations of 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), results in cell death. Recently, it has been reported that low concentrations of MPP+ induce apoptosis in susceptible neurons. We have further characterized MPP+-mediated toxicity of cultured cerebellar granule neurons (CGNs) and found that exposure of CGNs to relatively low concentrations of MPP+ results in apoptosis, whereas higher concentrations result in necrosis. Cotreatment of CGNs with MPP+ and the tetrapeptide inhibitor of caspase-3-like proteases, acetyl-DEVD-CHO, markedly attenuates apoptotic but not necrotic death of these neurons. The more specific inhibitor of caspase-1-like proteases, acetyl-YVAD-CHO, however, was ineffective against MPP+ neurotoxicity. Moreover, cytoplasmic extracts prepared from MPP+-treated CGNs contain markedly increased protease activity that cleaves the caspase-3 substrate acetyl-DEVD-p-nitroaniline. Finally, the cytoplasmic concentration of the apoptogenic protein cytochrome c was increased in a time-dependent fashion in MPP+-treated CGNs before the onset of apoptosis. Our data confirm that the neurotoxicity of MPP+ is due to both necrosis and apoptosis and suggest that the latter is mediated by activation of a caspase-3-like protease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.69041382.x
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  • 3
    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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  • 4
    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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  • 5
    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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  • 6
    Electronic Resource
    Electronic Resource
    A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression, secretion and cholesterol homeostasis in astrocytes (2004)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 88 (2004), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Apolipoprotein E (apoE) is an important protein involved in lipoprotein clearance and cholesterol redistribution. ApoE is abundantly expressed in astrocytes in the brain and is closely linked to the pathogenesis of Alzheimer's disease (AD). We report here that small molecule ligands that activate either liver X receptors (LXR) or retinoid X receptor (RXR) lead to a dramatic increase in apoE mRNA and protein expression as well as secretion of apoE in a human astrocytoma cell line (CCF-STTG1 cells). Examination of primary mouse astrocytes also revealed significant induction of apoE mRNA, and protein expression and secretion following incubation with LXR/RXR agonists. Moreover, treatment of mice with a specific synthetic LXR agonist T0901317 resulted in up-regulation of apoE mRNA and protein in both hippocampus and cerebral cortex, indicating that apoE expression in brain can be up-regulated by LXR agonists in vivo. Along with a dramatic induction of ABCA1 cholesterol transporter expression, these ligands effectively mediate cholesterol efflux in both CCF-STTG1 cells and mouse astrocytes in the presence or absence of apolipoprotein AI (apoAI). Our studies provide strong evidence that small molecule LXR/RXR agonists can effectively mediate apoE synthesis and secretion as well as cholesterol homeostasis in astrocytes. LXR/RXR agonists may have significant impact on the pathogenesis of multiple neurological diseases, including AD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02183.x
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  • 7
    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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  • 8
    Electronic Resource
    Electronic Resource
    Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides (2004)
    [s.l.] : Nature Publishing Group
    Nature medicine 10 (2004), S. 719-726 
    Details
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] We have previously shown that apolipoprotein E (Apoe) promotes the formation of amyloid in brain and that astrocyte-specific expression of APOE markedly affects the deposition of amyloid-β peptides (Aβ) in a mouse model of Alzheimer disease. Given the capacity of astrocytes to degrade ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/nm1058
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  • 9
    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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  • 10
    Electronic Resource
    Electronic Resource
    Apolipoprotein E affects the amount, form, and anatomical distribution of amyloid β-peptide deposition in homozygous APPV717F transgenic mice (2000)
    Springer
    Acta neuropathologica 100 (2000), S. 451-458 
    Details
    ISSN: 1432-0533
    Keywords: Key words Amyloid precursor protein ; Alzheimer’s ; disease ; Apolipoprotein E ; Hippocampus ; Transgenic mice
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Apolipoprotein E (apoE) has been implicated as a risk factor for Alzheimer’s disease and in the deposition, fibrillogenesis, and clearance of the amyloid β-peptide (Aβ). To examine the in vivo interactions between apoE and Aβ deposition, we examined 12-month-old transgenic (tg) mice expressing human amyloid precursor protein (APP) with the V717F mutation (APPV717F homozygous) on an APOE null background. Elimination of APOE resulted in a redistribution and alteration in the character of Aβ deposition in homozygous APPV717F tg mice, with a dramatic reduction in cortical and dentate gyrus deposition, prominent increase in diffuse CA1 and CA3 deposition, and prevention of the formation of thioflavin-S-positive deposits. These alterations in Aβ deposition were not mediated by significant changes in regional APP expression, low-density lipoprotein receptor-related protein expression, or soluble Aβ levels. Thus, apoE in APPV717F tg mice not only affects the amount and form of Aβ deposition, but also the anatomical distribution of diffuse Aβ deposits. The APPV717F tg mouse can serve as a model to investigate genetic influences on the vulnerability of specific neuroanatomical regions to Aβ deposition.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004010000263
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