Apolipoprotein E4 Potentiates Amyloid β Peptide-induced Lysosomal Leakage and Apoptosis in Neuronal Cells

Department of Medicine, University of California, San Francisco, San Francisco, California, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2002; 277(24):21821-8. DOI: 10.1074/jbc.M112109200
Source: PubMed


We assessed the isoform-specific effects of apolipoprotein (apo) E on the response of Neuro-2a cells to the amyloid beta peptide (Abeta1-42). As determined by the intracellular staining pattern and the release of beta-hexosaminidase into the cytosol, apoE4-transfected cells treated with aggregated Abeta1-42 showed a greater tendency toward lysosomal leakage than neo- or apoE3-transfected cells. Abeta1-42 caused significantly greater cell death and more than 2-fold greater DNA fragmentation in apoE4-secreting than in apoE3-secreting or control cells. H2O2 or staurosporine enhanced cell death and apoptosis in apoE4-transfected cells but not in apoE3-transfected cells. A caspase-9 inhibitor abolished the potentiation of Abeta1-42-induced apoptosis by apoE4. Similar results were obtained with conditioned medium from cells secreting apoE3 or apoE4. Cells preincubated for 4 h with a source of apoE3 or apoE4, followed by removal of apoE from the medium and from the cell surface, still exhibited the isoform-specific response to Abeta1-42, indicating that the potentiation of apoptosis required intracellular apoE, presumably in the endosomes or lysosomes. Studies of phospholipid (dimyristoylphosphatidylcholine) bilayer vesicles encapsulating 5-(and-6)-carboxyfluorescein dye showed that apoE4 remodeled and disrupted the phospholipid vesicles to a greater extent than apoE3 or apoE2. In response to Abeta1-42, vesicles containing apoE4 were disrupted to a greater extent than those containing apoE3. These findings are consistent with apoE4 forming a reactive molecular intermediate that avidly binds phospholipid and may insert into the lysosomal membrane, destabilizing it and causing lysosomal leakage and apoptosis in response to Abeta1-42.

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    • "Incubation with wild-type ApoE E3 or variant ApoE E4-enriched 3-VLDL results in differential cellular accumulation [Ji et al., 1998; Laws et al., 2003]. A two-to threefold increase in the accumulation of ApoE E3 over ApoE E4 has been observed in various cell types [Ji et al., 2002]. If mechanisms for proper clearance in the retina and Bruch's membrane are not in place, this accumulation may serve as a pathogenic basis for disease development [Ambati et al., 2003; Tuo et al., 2004b]. "
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    • "These polymorphic variants of apoE are encoded by three alleles of the same genomic locus. It has been observed that in neurons cultured in the presence of Aβ, the addition of exogenic apoE4 caused the leakage of lysosomes and activation of apoptotic processes, whereas the presence of apoE3 showed protective properties (Ji et al., 2002). Additionally, apoE4 had higher influence on the cell membrane instability than apoE3 (Ji et al., 2006). "
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    ABSTRACT: Metachromatic leukodystrophy (MLD) is a severe, neurodegenerative, metabolic disease which is caused by deficient activity of arylsulfatase A (ARSA). Sulfatides and other substrates of ARSA are stored in central and peripheral nervous systems, and in some other organs. Accumulated sulfatides are especially toxic to oligodendrocytes and Schwann cells leading to progressive demyelination. The kind of apolipoprotein E (apoE) isoform is of essential significance for the modulation of sulfatides quantity in the brain as apoE4 contains more sulfatides than apoE3. Taking into consideration the fact that apoE4 leads to the loss of sulfatides in CSF of Alzheimer disease patients, we examined if apoE isoforms display any impact on clinical outcome in patients with different forms of MLD in whom sulfatides accumulate. The significant association of age at onset of MLD symptoms with APOE ε2/ε3/ε4 and LRP1 c.766C>T polymorphisms was shown in multivariate stepwise regression analysis, in which other factors known to affect age at onset of the disease, i.e. clinical type of MLD, family connection of the patient and sex were also analyzed. As expected, the clinical type of MLD explained about 80% of the variance of the dependent variable. The impact of both polymorphisms on age of onset of the disease was considerably lower: 2.0% in the case of APOE polymorphism and 1.0% in the case of LRP1 polymorphism. Thus, the clinical outcome in MLD patients is related principally to the genotype of the ARSA gene, while the polymorphisms in the APOE and LRP1 genes are only slightly modifying factors.
    Gene 05/2013; 526(2). DOI:10.1016/j.gene.2013.05.009 · 2.14 Impact Factor
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    • "The main role of apolipoproteins A1, E and J in controlling the level of soluble β-amyloid peptide in the intra- and extracellular space of brain as well as their influence on oligomeric and fibrillar β-amyloid peptide generation is suggested. Apolipoprotein E increases β-amyloid peptide induced lysosomal leakage and apoptosis in neurons [102]. Apolipoproteins A1, E and J can influence the structure, toxicity, and accumulation of the β-amyloid peptide in postischemic brain. "
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