Oxidized High-Density Lipoprotein Induces Neuron Death

Keller, Jeffrey N.; Hanni, Keith B.; Kindy, Mark S.

doi:10.1006/exnr.1999.7276

Cited by 25 publications

(20 citation statements)

References 58 publications

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“…Amyloidogenic A␤ can mediate APP and APL P2 accumulation (Cribbs et al, 1995;Schmitt et al, 1997;White et al, 1998) and could result in Cu-mediated toxicity, particularly if associated with additional changes to Cu or lipoprotein metabolism (Keller et al, 1999(Keller et al, , 2000. Our findings may also have implications for other neurodegenerative disorders such as amyotrophic lateral sclerosis (AL S).…”

Section: Discussionmentioning

confidence: 74%

“…Whether APP Cu is able to induce direct or oxidized lipoprotein-mediated neuronal damage in vivo would depend on the availability of both Cu and lipoproteins. A potential role for oxidized lipoproteins in mediating neurodegeneration is supported by LDL being present in the brain as a result of cholesterol metabolism (Keller et al, 1999(Keller et al, , 2000, whereas high-density lipoprotein (HDL) is synthesized by glial cells and associated with amyloid plaques in AD (Harr et al, 1996;Markesbery, 1997;Yamada et al, 1997). In addition, the expression of the apolipoprotein E4, a risk factor for AD, can promote APP secretion (Howland et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the expression of the apolipoprotein E4, a risk factor for AD, can promote APP secretion (Howland et al, 1998). Interestingly, lipoproteins derived from AD CSF fluid reveal a higher level of oxidation than control lipoproteins (Bassett et al, 1999(Bassett et al, , 2000Schippling et al, 2000) and Cu-oxidized LDL and HDL induce neuronal cell death in vitro (Dubbing 1963;Kabara 1973;Pitas et al, 1987;Keller et al, 1999Keller et al, , 2000. Significantly, cerebral cortex and hippocampus from a transgenic mouse model of AD amyloidosis reveal increased LPO compared with wild-type mice well before the appearance of A␤ plaques (Praticò et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

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Contrasting, Species-Dependent Modulation of Copper-Mediated Neurotoxicity by the Alzheimer's Disease Amyloid Precursor Protein

et al. 2002

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The amyloid precursor protein (APP) of Alzheimer's disease (AD) has a copper binding domain (CuBD) located in the N-terminal cysteine-rich region that can strongly bind copper(II) and reduce it to Cu(I) in vitro. The CuBD sequence is similar among the APP family paralogs [amyloid precursor-like proteins (APLP1 and APLP2)] and its orthologs (including Drosophila melanogaster, Xenopus laevis, and Caenorhabditis elegans), suggesting an overall conservation in its function or activity. The APP CuBD is involved in modulating Cu homeostasis and amyloid ␤ peptide production. In this paper, we demonstrate for the first time that Cu-metallated full-length APP ectodomain induces neuronal cell death in vitro. APP Cu neurotoxicity can be induced directly or potentiated through Cu(I)-mediated oxidation of low-density lipoprotein, a finding that may have important implications for the role of lipoproteins and membrane cholesterol composition in AD. Cu toxicity induced by human APP, Xenopus APP, and APLP2 CuBDs is dependent on conservation of histidine residues at positions corresponding to 147 and 151 of human APP. Intriguingly, APP orthologs with different amino acid residues at these positions had dramatically altered Cu phenotypes. The corresponding C. elegans APL-1 CuBD, which has tyrosine and lysine residues at positions 147 and 151, respectively, strongly protected against Cu-mediated lipid peroxidation and neurotoxicity in vitro. Replacement of histidines 147 and 151 with tyrosine and lysine residues conferred this neuroprotective Cu phenotype to human APP, APLP2, and Xenopus APP CuBD peptides. Moreover, we show that the toxic and protective CuBD phenotypes are associated with differences in Cu binding and reduction. These studies identify a significant evolutionary change in the function of the CuBD in modulating Cu metabolism. Our findings also suggest that targeting of inhibitors to histidine residues at positions 147 and 151 of APP could significantly alter the oxidative potential of APP.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Contrasting, Species-Dependent Modulation of Copper-Mediated Neurotoxicity by the Alzheimer's Disease Amyloid Precursor Protein

et al. 2002

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“…Dildar et al (2010) also found that plasma ox-LDL was not related to plasma 3-NT level in AD patients. In contrast, Sinem et al (2010) found that plasma ox-LDL in AD patients was positively related to plasma 3-NT level, which may be because ox-LDL can increase oxidation activity, promote the proliferation of astrocyte cells, microglia cells, and inflammatory cytokines, which in turn exacerbate oxidative stress and stress-related nitration (Keller et al, 1999(Keller et al, , 2000Hsiai et al, 2007).…”

Section: Discussionmentioning

confidence: 93%

Expression and significance of plasma 3-NT and ox-LDL in patients with Alzheimer's disease

Zhi-gang¹,

Zhou²,

Peng³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. To examine the expression and clinical significance of plasma 3-nitrotyrosine (3-NT) and oxidized low-density lipoprotein (ox-LDL) levels in patients with Alzheimer's disease (AD), we examined 48 AD patients and 37 healthy control subjects. The Mini-Mental State Examination, Activities of Daily Living Scale, and Hachinski Ischemic Scale were examined in all subjects. AD patients were classified using the Global Deterioration Scale. The concentrations of plasma 3-NT and ox-LDL were detected using an enzyme-linked immunosorbent assay. We found that the plasma 3-NT concentration in the AD group (119.46 ± 21.82 nM) was significantly higher than that in the control group (55.09 ± 9.63 nM) (P < 0.05). Spearman analysis showed that plasma 3-NT level was negatively associated with the Mini-Mental State Examination results of AD patients. Plasma ox-LDL level in the AD group (112.25 ± 17.81 mg/L) was significantly higher than that in the control group (47.46 ± 10.04 mg/L) (P < 0.05). Spearman analysis showed that plasma ox-LDL level was positively correlated with AD severity in AD patients. However, plasma 3-NT level in the AD group was not associated with plasma ox-LDL level. Therefore, plasma 3-NT 8429©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 13 (4): 8428-8435 (2014) NT and ox-LDL in Alzheimer's disease and ox-LDL levels in AD patients were significantly increased, which may be related to the degree of AD severity in AD patients.

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“…These lipoproteins can possibly mediate the effects upon cells in the brain during times of oxidative stress or compromised BBB. Keller et al (1999) reported that oxidized lipoproteins increase ROS formation, and because ROS are associated with numerous astrocyte and microglia activities including proliferation, activation, and cytokine production, it is possible that lipoproteins may mediate such effects on glial cells in the CNS (Keller et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Lipoproteins Obtained from Anorexia Nervosa Patients Induce Higher Oxidative Stress in U373MG Astrocytes Through Nitric Oxide Production

et al. 2007

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Eating disorders (ED) are a group of important psychiatric disorders that affect young men and women, and can have serious consequences. Among all ED, anorexia nervosa (AN) is the most typical but also the most severe. The pathogenesis of AN is multifactorial and a great variety of cognitive deficits may contribute to its pathogenesis. The present study is aimed to measure NO and peroxynitrite production, iNOS and nNOS expression by Western immunoblot after incubation of AN lipoproteins at different times with human astrocytoma cells. The AN-HDL treated cells showed an increased production of NO at 3 h versus control-HDL treated cells and a decreased production at 24 h. Regarding LDL, a significant increase of NO production was obtained both at 3 and 24 h. The AN-HDL and AN-LDL treated cells showed an increased production of peroxynitrite both at 3 and 24 h compared to control lipoproteins. Densitometric analysis of bands indicated that both iNOS and nNOS protein levels were significantly higher in the cells incubated with AN lipoproteins compared to cells incubated with control lipoproteins both at 3 and 24 h. Although the pathogenesis of AN remains uncertain, evidence exists that modifications to the lipoprotein profile and cholesterol, structural alterations of phospholipids and integral constituents of myelin and synaptosomes may be related to psychotic disorders and body image distortion common to AN. Thus, a relevant pathophysiological association between NO and depression is certainly a possibility, as well as a central role played by NO in the pathogenesis.

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Oxidized High-Density Lipoprotein Induces Neuron Death

Cited by 25 publications

References 58 publications

Contrasting, Species-Dependent Modulation of Copper-Mediated Neurotoxicity by the Alzheimer's Disease Amyloid Precursor Protein

Contrasting, Species-Dependent Modulation of Copper-Mediated Neurotoxicity by the Alzheimer's Disease Amyloid Precursor Protein

Expression and significance of plasma 3-NT and ox-LDL in patients with Alzheimer's disease

Lipoproteins Obtained from Anorexia Nervosa Patients Induce Higher Oxidative Stress in U373MG Astrocytes Through Nitric Oxide Production

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