Redox status of serum apolipoprotein E and its impact on HDL cholesterol levels

Yamauchi, Kazuyoshi; Ebihara, Yuka; Kawakami, Yasushi

doi:10.1016/j.clinbiochem.2017.03.021

Cited by 14 publications

(24 citation statements)

References 32 publications

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“…The redox status of apoE was analyzed with a band-shift assay using polyethylene glycol maleimide (PEG-PC-Mal), according to our previous study [17]. Briefly, PEG-PC-Mal was added to the sample at a final concentration of 1.0 mmol/l.…”

Section: Methodsmentioning

confidence: 99%

“…The specific bands were developed using an ECL detection kit (Nacalai Tesque, Inc., Kyoto, Japan), and were analyzed using ImageJ 1.45 software from the National Institutes of Health. As previously described [17], a 40-kDa labeled apoE3 was defined as the reduced form (r) of apoE3, while the monomeric form (35-kDa unlabeled apoE3) remaining in the presence of PEG-PC-Mal was termed as the non-reduced form (nr) of apoE3 (Figure 1). In addition to these bands, as previous studies have well confirmed [6,9], the bands with molecular masses of 47.0 and 95.0 kDa were defined as the apoE3-AII and homodimer, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…To date, several studies have suggested that the redox status of cysteine thiol may greatly affect various biological activities [14–16]. We have recently suggested that the redox status of serum apoE may depend on its cysteine thiol modification and is closely related to the synthesis of HDL [17].…”

Section: Introductionmentioning

confidence: 99%

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Redox equilibrium of serum apolipoprotein E3: a buffering effect of disulfide-linked complexes against oxidative stress on apolipoprotein E3–containing lipoproteins

2019

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Reversible redox modification of cysteine thiols is crucial for protecting proteins from irreversible detrimental change. However, the physiological significance of the redox modification of apolipoprotein (apo) E is unclear. Here, we hypothesized that the disulfide-linked complexes of apoE3 corresponding to the representative reversible-modified apoE3 play a protective role against oxidative stress. The effects of disulfide bond formation on oxidative stress on apoE3 were evaluated with a band-shift assay. Maleimide-labeled apoE3 and unlabeled apoE3 were defined as the reduced (r)-apoE3 and non-reduced (nr)-apoE3 forms, respectively. Hydrogen peroxide-induced oxidation decreased for reduced-form apoE (r-apoE3) but increased for nr-apoE3. Induction of apoE3-AII complex formation with excess of apoAII markedly suppressed the oxidative stress-induced increase in nr-apoE3 (P<0.001) and enhanced homodimer formation. The apoE3-AII complex was more dominant in high-density lipoprotein (HDL) than in very low-density lipoprotein. Under oxidative stress, HDL showed a significant decrease, rather than an increase, in nr-apoE3 levels with a concomitant significant increase in apoE3-AII levels (P<0.005). This finding suggests that the majority of nr-apoE3 in HDL exists in a reversible oxidized form. The apoE3-AII complex, formed from the reversible oxidized apoE3, is beneficial for maintaining the redox equilibrium of apoE3 by preventing the modification of apoE3 to its irreversible oxidized form. The apoE3-AII complex may be possibly implicated in the pathophysiology of various apoE-related diseases.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Redox equilibrium of serum apolipoprotein E3: a buffering effect of disulfide-linked complexes against oxidative stress on apolipoprotein E3–containing lipoproteins

2019

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“…Indeed, ApoEε3 is less likely to be retained at the ER (Brodbeck et al, 2011), and although the retention of ApoEε2 in the ER has not been reported, the effect of ER retention is due to the S61R present in ApoEε3 and ApoEε4, but not present in ApoEε2, thus making ApoEε2 far less likely to be retained at the ER. Perhaps the additional cysteine residues in ApoEε2 compared with ApoEε3 or ApoEε4 make ApoEε2 an agent of redox stabilization at mitochondria during stress (Yamauchi et al, 2017). Additionally, variations in the translocase of outer mitochondrial membrane 40 (TOMM40) and ApoE are associated with differences in longevity (Lin et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

ApoE-associated modulation of neuroprotection from Aβ-mediated neurodegeneration in transgenic Caenorhabditis elegans

Griffin

Scopel

Stephen

et al. 2019

Disease Models &Amp; Mechanisms

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Allele-specific distinctions in the human apolipoprotein E ( APOE ) locus represent the best-characterized genetic predictor of Alzheimer's disease (AD) risk. Expression of isoform APOE ε2 is associated with reduced risk, while APOE ε3 is neutral and APOE ε4 carriers exhibit increased susceptibility. Using Caenorhabditis elegans , we generated a novel suite of humanized transgenic nematodes to facilitate neuronal modeling of amyloid-beta peptide (Aβ) co-expression in the context of distinct human APOE alleles. We found that co-expression of human APOE ε2 with Aβ attenuated Aβ-induced neurodegeneration, whereas expression of the APOE ε4 allele had no effect on neurodegeneration, indicating a loss of neuroprotective capacity. Notably, the APOE ε3 allele displayed an intermediate phenotype; it was not neuroprotective in young adults but attenuated neurodegeneration in older animals. There was no functional impact from the three APOE isoforms in the absence of Aβ co-expression. Pharmacological treatment that examined neuroprotective effects of APOE alleles on calcium homeostasis showed allele-specific responses to changes in ER-associated calcium dynamics in the Aβ background. Additionally, Aβ suppressed survival, an effect that was rescued by APOE ε2 and APOE ε3, but not APOE ε4. Expression of the APOE alleles in neurons, independent of Aβ, exerted no impact on survival. Taken together, these results illustrate that C. elegans provides a powerful in vivo platform with which to explore how AD-associated neuronal pathways are modulated by distinct APOE gene products in the context of Aβ-associated neurotoxicity. The significance of both ApoE and Aβ to AD highlights the utility of this new pre-clinical model as a means to dissect their functional inter-relationship.

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“…ApoE2 has cysteine residues at positions 112 and 158, which can undergo reversible thiol oxidation in response to the intracellular redox environment. Pertinently, these thiol modifications enable ApoE2 to form disulfide-linked homodimers and higher-order oligomers (69)(70)(71), which would explain the increase in ApoE2 condensate volumes. In agreement with this model, ApoE3, which has a cysteine at 112 and an arginine at 158, is predicted to have fewer phase transitions under oxidative stress; however, thiol modification at 112 could presumably explain the small increase in condensate formation we observed in Figure 4F.…”

Section: Apoe2 Undergoes Aberrant Phase Transitions To Form Biomolecumentioning

confidence: 99%

Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration

Cunza

Tan

Thamban

et al. 2020

Preprint

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The retinal pigment epithelium (RPE) is the site of initial damage leading to photoreceptor degeneration and vision loss in age-related macular degeneration (AMD). Genetic and histopathological studies implicate cholesterol dysregulation in AMD; yet mechanisms linking cholesterol to RPE injury and drusen formation remain poorly understood. Especially enigmatic are allelic variants of the cholesterol transporter APOE, major risk modifiers in Alzheimer’s disease that show reversed risk associations with AMD. Here, we investigated how ApoE isoforms modulate RPE health using live-cell imaging of primary RPE cultures and high-resolution imaging of human donor tissue. We show that the AMD-protective ApoE4 efficiently transports cholesterol and safeguards RPE homeostasis despite cellular stress. In contrast, ApoE2-expressing RPE accumulate cholesterol, which promotes autophagic deficits and complement-mediated mitochondrial fragmentation. Redox-related order-disorder phase transitions in ApoE2 drive the formation of intracellular biomolecular condensates as potential drusen precursors. Drugs that restore mitochondrial function limit condensate formation in ApoE2-RPE. Autophagic and mitochondrial defects correlate with intracellular ApoE aggregates in AMD donor RPE. Our study elucidates how AMD risk variants act as tipping points to divert the RPE from normal aging towards AMD by disrupting critical metabolic functions, and identifies mitochondrial stress-mediated aberrant phase transitions as a novel mechanism of drusen biogenesis.

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Redox status of serum apolipoprotein E and its impact on HDL cholesterol levels

Cited by 14 publications

References 32 publications

Redox equilibrium of serum apolipoprotein E3: a buffering effect of disulfide-linked complexes against oxidative stress on apolipoprotein E3–containing lipoproteins

Redox equilibrium of serum apolipoprotein E3: a buffering effect of disulfide-linked complexes against oxidative stress on apolipoprotein E3–containing lipoproteins

ApoE-associated modulation of neuroprotection from Aβ-mediated neurodegeneration in transgenic Caenorhabditis elegans

Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration

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