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  • 1
    Electronic Resource
    Electronic Resource
    Expanding the association between the APOE gene and the risk of Alzheimer's disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription (2003)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 84 (2003), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Alzheimer's disease (AD) is the most commonly diagnosed form of dementia in the elderly. Predominantly this disease is sporadic in nature with only a small percentage of patients exhibiting a familial trait. Early-onset AD may be explained by single gene defects; however, most AD cases are late onset (〉 65 years) and, although there is no known definite cause for this form of the disease, there are several known risk factors. Of these, the ε4 allele of the apolipoprotein E (apoE) gene (APOE) is a major risk factor. The ε4 allele of APOE is one of three (ɛ2 ɛ3 and ɛ4) common alleles generated by cysteine/arginine substitutions at two polymorphic sites. The possession of the ɛ4 allele is recognized as the most common identifiable genetic risk factor for late-onset AD across most populations. Unlike the pathogenic mutations in the amyloid precursor or those in the presenilins, APOEɛ4 alleles increase the risk for AD but do not guarantee disease, even when present in homozygosity. In addition to the cysteine/arginine polymorphisms at the ɛ2/ɛ3/ɛ4 locus, polymorphisms within the proximal promoter of the APOE gene may lead to increased apoE levels by altering transcription of the APOE gene. Here we review the genetic and biochemical evidence supporting the hypothesis that regulation of apoE protein levels may contribute to the risk of AD, distinct from the well known polymorphisms at the ɛ2/ɛ3/ɛ4 locus.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2003.01615.x
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  • 2
    Electronic Resource
    Electronic Resource
    The Phosphatidylinositol 3-Kinase Inhibitor Wortmannin Alters the Metabolism of the Alzheimer's Amyloid Precursor Protein (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 : One of the hallmarks of Alzheimer's disease is the accumulation of senile plaques in brain, extracellular lesions comprised mostly of aggregates of the amyloid β-peptide (Aβ). Aβ is proteolytically derived from the Alzheimer's amyloid precursor protein (APP). The generation of Aβ and nonamyloidogenic derivatives of APP involves utilization of alternative processing pathways and multiple subcellular compartments. To improve our understanding of the regulation of APP processing, we investigated the effects of wortmannin, a phosphatidyl-inositol 3-kinase (PI3-kinase) inhibitor, on APP processing. PI3-kinases form a multifaceted family of enzymes that represent converging points for multiple signal transduction pathways and also act as key regulators of vesicular trafficking. In N2a neuroblastoma cells expressing either wild-type APP or the “Swedish” familial Alzheimer's disease-associated mutant variant of APP, wortmannin treatment resulted in decreased release of both Aβ and soluble APPα. In parallel, full-length APP and both processed derivatives accumulated inside the cells. These effects were not present at nanomolar concentrations of wortmannin, but only at micromolar concentrations, implying the possible involvement of a recently described trans-Golgi network (TGN)-associated PI3-kinase that is resistant to nanomolar concentrations of the inhibitor, but sensitive to micromolar concentrations. All effects were reversible when the drug was removed from the cell culture medium. Given the suspected site of action of this novel PI3-kinase activity at the TGN, it is tempting to speculate that the unexpected increase in the levels of both intracellular soluble APPα and intracellular Aβ might be due to wortmannin-induced covesiculation of APP together with its respective secretase enzymes within the TGN, leading to the execution of α-, β-, and γ-secretase reactions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0732316.x
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  • 3
    Electronic Resource
    Electronic Resource
    Mutant Presenilin 1 Increases the Levels of Alzheimer Amyloid β-Peptide Aβ42 in Late Compartments of the Constitutive Secretory Pathway (2000)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 74 (2000), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Mutations in the presenilin 1 (PS1) gene are associated with autosomal dominant, early-onset, familial Alzheimer's disease and result in increased release of the hyperaggregatable 42-amino acid form of the amyloid β-peptide (Aβ42). To determine which subcellular compartments are potential source(s) of released Aβ42, we compared the levels and spatial segregation of intracellular Aβ40 and Aβ42 peptides between N2a neuroblastoma cells doubly transfected with the “Swedish” familial Alzheimer's disease-linked amyloid precursor protein variant and either wild-type PS1 (PS1wt) or familial Alzheimer's disease-linked Δ9 mutant PS1 (PS1Δ9). As expected, PS1Δ9-expressing cells had dramatically higher levels of intracellular Aβ42 than did cells expressing PS1wt. However, the highest levels of Aβ42 colocalized not with endoplasmic reticulum or Golgi markers but with rab8, a marker for trans-Golgi network (TGN)-to-plasma membrane (PM) transport vesicles. We show that PS1 mutants are capable of causing accumulation of Aβ42 in late compartments of the secretory pathway, generating there a readily releasable source of Aβ42. Our findings indicate that PS1 “bioactivity” localizes to the vicinity of the TGN and/or PM and reconcile the apparent discrepancy between the preponderant concentration of PS1 protein in proximal compartments of the secretory pathway and the recent findings that PS1 “bioactivity” can control γ-secretase-like processing of another trans-membrane substrate, Notch, at or near the PM.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2000.0741878.x
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  • 4
    Electronic Resource
    Electronic Resource
    Generation and Regulation of β-Amyloid Peptide Variants by Neurons (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 71 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Studies of processing of the Alzheimer β-amyloid precursor protein (βAPP) have been performed to date mostly in continuous cell lines and indicate the existence of two principal metabolic pathways: the “β-secretase” pathway, which generates β-amyloid (Aβ1–40/42; ∼4 kDa), and the “α-secretase” pathway, which generates a smaller fragment, the “p3” peptide (Aβ17–40/42; ∼3 kDa). To determine whether similar processing events underlie βAPP metabolism in neurons, media were examined following conditioning by primary neuronal cultures derived from embryonic day 17 rats. Immunoprecipitates of conditioned media derived from [35S]methionine pulse-labeled primary neuronal cultures contained 4- and 3-kDa Aβ-related species. Radiosequencing analysis revealed that the 4-kDa band corresponded to conventional Aβ beginning at position Aβ(Asp1), whereas both radio-sequencing and immunoprecipitation-mass spectrometry analyses indicated that the 3-kDa species in these conditioned media began with Aβ(Glu11) at the N terminus, rather than Aβ(Leu17) as does the conventional p3 peptide. Either activation of protein kinase C or inhibition of protein phosphatase 1/2A increased soluble βAPPα release and decreased generation of both the 4-kDa Aβ and the 3-kDa N-truncated Aβ. Unlike results obtained with continuously cultured cells, protein phosphatase 1/2A inhibitors were more potent at reducing Aβ secretion by neurons than were protein kinase C activators. These data indicate that rodent neurons generate abundant Aβ variant peptides and emphasize the role of protein phosphatases in modulating neuronal Aβ generation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.71051920.x
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  • 5
    Electronic Resource
    Electronic Resource
    Atorvastatin-induced activation of Alzheimer's α secretase is resistant to standard inhibitors of protein phosphorylation-regulated ectodomain shedding (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: Studies of metabolism of the Alzheimer amyloid precursor protein (APP) have focused much recent attention on the biology of juxta- and intra-membranous proteases. Release or ‘shedding’ of the large APP ectodomain can occur via one of two competing pathways, the α- and β-secretase pathways, that are distinguished both by subcellular site of proteolysis and by site of cleavage within APP. The α-secretase pathway cleaves within the amyloidogenic Aβ domain of APP, precluding the formation of toxic amyloid aggregates. The relative utilization of the α- and β-secretase pathways is controlled by the activation of certain protein phosphorylation signal transduction pathways including protein kinase C (PKC) and extracellular signal regulated protein kinase [ERK/mitogen-activated protein kinase (MAP kinase)], although the relevant substrates for phosphorylation remain obscure. Because of their apparent ability to decrease the risk for Alzheimer disease, the effects of statins (HMG CoA reductase inhibitors) on APP metabolism were studied. Statin treatment induced an APP processing phenocopy of PKC or ERK activation, raising the possibility that statin effects on APP processing might involve protein phosphorylation. In cultured neuroblastoma cells transfected with human Swedish mutant APP, atorvastatin stimulated the release of α-secretase-released, soluble APP (sAPPα). However, statin-induced stimulation of sAPPα release was not antagonized by inhibitors of either PKC or ERK, or by the co-expression of a dominant negative isoform of ERK (dnERK), indicating that PKC and ERK do not play key roles in mediating the effect of atorvastatin on sAPPα secretion. These results suggest that statins may regulate α-secretase activity either by altering the biophysical properties of plasma membranes or by modulating the function of as-yet unidentified protein kinases that respond to either cholesterol or to some intermediate in the cholesterol metabolic pathway. A ‘phospho-proteomic’ analysis of N2a cells with and without statin treatment was performed, revealing changes in the phosphorylation state of several protein kinases plausibly related to APP processing. A systematic evaluation of the possible role of these protein kinases in statin-regulated APP ectodomain shedding is underway.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02521.x
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  • 6
    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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  • 7
    Electronic Resource
    Electronic Resource
    Use of Cultured Fibroblasts in Elucidating the Pathophysiology and Diagnosis of Alzheimer's Disease (1994)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 747 (1994), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1994.tb44412.x
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  • 8
    Electronic Resource
    Electronic Resource
    Estrogen reduces neuronal generation of Alzheimer β-amyloid peptides (1998)
    [s.l.] : Nature Publishing Group
    Nature medicine 4 (1998), S. 447-451 
    Details
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Alzheimer's disease (AD) is characterized by the accumulation of cerebral plaques composed of 40- and 42-amino acid β-amyloid (Aβ) peptides, and autosomal dominant forms of AD appear to cause disease by promoting brain Aβ accumulation. Recent studies indicate that postmenopausal ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/nm0498-447
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  • 9
    Electronic Resource
    Electronic Resource
    Alzheimer disease: presenilin springs a leak (2006)
    [s.l.] : Nature Publishing Group
    Nature medicine 12 (2006), S. 1121-1123 
    Details
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Several proteins are believed to be essential for the pathology of Alzheimer disease. Two of these proteins—presenilins—are involved in a cleavage reaction that generates key protein fragments, known collectively as amyloid-β peptides. According to this “amyloid ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/nm1006-1121
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  • 10
    Electronic Resource
    Electronic Resource
    Alzheimer's disease Molecular consequences of presenilin-1 mutation (2001)
    [s.l.] : Nature Publishing Group
    Nature 411 (2001), S. 654-655 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Alzheimer's disease is characterized by accumulation in the brain of a family of insoluble amyloid peptides (Aβ peptides), which are produced as a result of the normal processing of β-amyloid precursor protein (β-APP). Russo et al. claim that a truncated Aβ peptide that ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/35079682
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