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  • 1
    Electronic Resource
    Electronic Resource
    Aging, gender and APOE isotype modulate metabolism of Alzheimer's Aβ peptides and F2-isoprostanes in the absence of detectable amyloid deposits (2004)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 90 (2004), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Aging and apolipoprotein E (APOE) isoform are among the most consistent risks for the development of Alzheimer's disease (AD). Metabolic factors that modulate risk have been elusive, though oxidative reactions and their by-products have been implicated in human AD and in transgenic mice with overt histological amyloidosis. We investigated the relationship between the levels of endogenous murine amyloid β (Aβ) peptides and the levels of a marker of oxidation in mice that never develop histological amyloidosis [i.e. APOE knockout (KO) mice with or without transgenic human APOEɛ3 or human APOEɛ4 alleles]. Aging-, gender-, and APOE-genotype-dependent changes were observed for endogenous mouse brain Aβ40 and Aβ42 peptides. Levels of the oxidized lipid F2-isoprostane (F2-isoPs) in the brains of the same animals as those used for the Aβ analyses revealed aging- and gender-dependent changes in APOE KO and in human APOEɛ4 transgenic KO mice. Human APOEɛ3 transgenic KO mice did not exhibit aging- or gender-dependent increases in F2-isoPs. In general, the changes in the levels of brain F2-isoPs in mice according to age, gender, and APOE genotype mirrored the changes in brain Aβ levels, which, in turn, paralleled known trends in the risk for human AD. These data indicate that there exists an aging-dependent, APOE-genotype-sensitive rise in murine brain Aβ levels despite the apparent inability of the peptide to form histologically detectable amyloid. Human APOEɛ3, but not human APOEɛ4, can apparently prevent the aging-dependent rise in murine brain Aβ levels, consistent with the relative risk for AD associated with these genotypes. The fidelity of the brain Aβ/F2-isoP relationship across multiple relevant variables supports the hypothesis that oxidized lipids play a role in AD pathogenesis, as has been suggested by recent evidence that F2-isoPs can stimulate Aβ generation and aggregation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02532.x
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  • 2
    Electronic Resource
    Electronic Resource
    α2-Macroglobulin Complexes with and Mediates the Endocytosis of β-Amyloid Peptide via Cell Surface Low-Density Lipoprotein Receptor-Related 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: A primary histopathological feature of Alzheimer's disease is the accumulation of β-amyloid (Aβ) in the brain of afflicted individuals. However, Aβ is produced continuously as a soluble protein in healthy individuals where it is detected in serum and CSF, suggesting the existence of cellular clearance mechanisms that normally prevent its accumulation and aggregation. Here, we demonstrate that Aβ forms stable complexes with activated α2-macroglobulin (α2M⋆), a physiological ligand for the low-density lipoprotein receptor-related protein (LRP) that is abundantly expressed in the CNS. These α2M⋆/125I-Aβ complexes are immunoreactive with both anti-Aβ and anti-α2M IgG and are stable under various pH conditions, sodium dodecyl sulfate, reducing agents, and boiling. We demonstrate that α2M⋆/125I-Aβ complexes can be degraded by glioblastoma cells and fibroblasts via LRP, because degradation is partially inhibited by receptor-associated protein (RAP), an antagonist of ligand interactions with LRP. In contrast, the degradation of free 125I-Aβ is not inhibited by RAP and thus must be mediated via an LRP-independent pathway. These results suggest that LRP can function as a clearance receptor for Aβ via a physiological ligand.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.69051904.x
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  • 3
    Electronic Resource
    Electronic Resource
    Plasmalogen deficiency in early Alzheimer's disease subjects and in animal models: molecular characterization using electrospray ionization mass spectrometry (2001)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 77 (2001), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: To explore the hypothesis that alterations in ethanolamine plasmalogen may be directly related to the severity of dementia in Alzheimer's disease (AD), we performed a systematic examination of plasmalogen content in cellular membranes of gray and white matter from different regions of human subjects with a spectrum of AD clinical dementia ratings (CDR) using electrospray ionization mass spectrometry (ESI/MS). The results demonstrate: (1) a dramatic decrease in plasmalogen content (up to 40 mol% of total plasmalogen) in white matter at a very early stage of AD (i.e. CDR 0.5); (2) a correlation of the deficiency in gray matter plasmalogen content with the AD CDR (i.e. ∼10 mol% of deficiency at CDR 0.5 (very mild dementia) to ∼30 mol% of deficiency at CDR 3 (severe dementia); (3) an absence of alterations of plasmalogen content and molecular species in cerebellar gray matter at any CDR despite dramatic alterations of plasmalogen content in cerebellar white matter. Alterations of ethanolamine plasmalogen content in two mouse models of AD, APPV717F and APPsw, were also examined by ESI/MS. A plasmalogen deficiency was present (up to 10 mol% of total plasmalogen at the age of 18 months) in cerebral cortices, but was absent in cerebella from both animal models. These results suggest plasmalogen deficiency may play an important role in the AD pathogenesis, particularly in the white matter, and suggest that altered plasmalogen content may contribute to neurodegeneration, synapse loss and synaptic dysfunction in AD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2001.00332.x
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  • 4
    Electronic Resource
    Electronic Resource
    The Low-Density Lipoprotein Receptor-Related Protein, a Multifunctional Apolipoprotein E Receptor, Modulates Hippocampal Neurite Development (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 68 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The ε4 allele of apolipoprotein E (apoE) is an important risk factor for Alzheimer's disease. A major neuronal receptor for apoE within the brain is the low-density lipoprotein receptor-related protein (LRP). Using primary cultured hippocampal neurons, we examined the role of LRP in early neuronal development. LRP, as well as a 39-kDa protein that regulates its activity, is localized abundantly in developing neurons. Both the 39-kDa protein and an anti-LRP antibody inhibited neurite outgrowth of primary hippocampal neurons cultured in either serum-containing medium or on cortical astrocyte monolayers in serum-free medium. It is noteworthy that microtubule-associated protein-2 immunoreactive process outgrowth was decreased significantly in hippocampal neurons cultured on cortical astrocytes derived from apoE-deficient mice and was not diminished further following incubation with LRP inhibitors. Thus, these results suggest that LRP can influence aspects of neuronal process development and that apoE-containing lipoproteins may be one of the major LRP ligands that can contribute to this process.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.68020587.x
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  • 5
    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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  • 6
    Electronic Resource
    Electronic Resource
    No effect of apolipoprotein E on neuronal cell death due to excitotoxic and apoptotic agents in vitro and neonatal hypoxic ischaemia in vivo (2000)
    Oxford, UK : Blackwell Science Ltd
    European journal of neuroscience 12 (2000), S. 0 
    Details
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The ε4 allele of apolipoprotein E (apoE) is a genetic risk factor for Alzheimer's disease. Studies also suggest that the ε4 allele may be a risk factor for poor outcome following head trauma, brain haemorrhage and ischaemia. The mechanism by which the presence of an apoE ε4 allele and certain brain injuries act to predispose to Alzheimer's disease and poor outcome following brain injury is unknown. We questioned whether poor outcome after brain injury was due to direct modification by apoE protein and its gene variants of susceptibility to glutamate-mediated excitotoxic injury and apoptosis, mechanisms of cell death which occur following ischaemia and trauma. We investigated the effect of the presence or absence of endogenous murine apoE protein and different apoE isoforms in modification of the survival of murine embryonic cortical neurons exposed to the glutamate agonist, N-methyl- d-aspartic acid (NMDA) or apoptotic insult by staurosporine, and on the amount of brain injury sustained following a hypoxic-ischaemic insult in vivo to the brain of neonatal mice transgenically expressing human apoE ε3 or ε4. Our data provide evidence that apoE does not appear to alter neuronal viability following diverse types of acute neuronal insult, e.g. hypoxic-ischaemic or acute exposure to injurious agents in the models we have examined. This suggests that if apoE does modify the extent of brain damage and recovery after injury, it seems unlikely to be a result of direct or indirect modulation of excitotoxic or apoptotic cell death.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1460-9568.2000.00113.x
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  • 7
    Electronic Resource
    Electronic Resource
    Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo (2006)
    [s.l.] : Nature Publishing Group
    Nature medicine 12 (2006), S. 856-861 
    Details
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Certain disease states are characterized by disturbances in production, accumulation or clearance of protein. In Alzheimer disease, accumulation of amyloid-β (Aβ) in the brain and disease-causing mutations in amyloid precursor protein or in enzymes that produce Aβ indicate ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/nm1438
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  • 8
    Electronic Resource
    Electronic Resource
    Caspases: A treatment target for neurodegenerative disease? (1997)
    [s.l.] : Nature Publishing Group
    Nature medicine 3 (1997), S. 954-955 
    Details
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] CELLULAR GROWTH AND proliferation are clearly necessary for development of the nervous system. In addition, programmed cell death (PCD)/apoptosis is also important in molding the nervous system's final appearance and function. Between 20% and 80% of the neurons of the central nervous ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/nm0997-954
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  • 9
    Electronic Resource
    Electronic Resource
    Reply to “Inhibition of post-ischemic brain injury by clusterin overexpression” (2001)
    [s.l.] : Nature Publishing Group
    Nature medicine 7 (2001), S. 978-979 
    Details
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Holtzman and colleagues reply We recently reported that Clu−/− mice sustain less brain injury in a murine model of neonatal hypoxia-ischemia (H-I), and also that clusterin appeared to influence caspase-3–independent death in this model. Clusterin accumulated in some dying neurons ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/nm0901-978
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  • 10
    Electronic Resource
    Electronic Resource
    Clusterin contributes to caspase-3–independent brain injury following neonatal hypoxia-ischemia (2001)
    [s.l.] : Nature Publishing Group
    Nature medicine 7 (2001), S. 338-343 
    Details
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Clusterin, also known as apolipoprotein J, is a ubiquitously expressed molecule thought to influence a variety of processes including cell death. In the brain, it accumulates in dying neurons following seizures and hypoxic-ischemic (H-I) injury. Despite this, in vivo evidence that clusterin ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/85487
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