Selective reduction of hydroperoxyeicosatetraenoic acids to their hydroxy derivatives by apolipoprotein D: implications for lipid antioxidant activity and Alzheimer's disease

Abstract

ApoD (apolipoprotein D) is up-regulated in AD (Alzheimer's disease) and upon oxidative stress. ApoD inhibits brain lipid peroxidation in vivo, but the mechanism is unknown. Specific methionine residues may inhibit lipid peroxidation by reducing radical-propagating L-OOHs (lipid hydroperoxides) to non-reactive hydroxides via a reaction that generates MetSO (methionine sulfoxide). Since apoD has three conserved methionine residues (Met(49), Met(93) and Met(157)), we generated recombinant proteins with either one or all methionine residues replaced by alanine and assessed their capacity to reduce HpETEs (hydroperoxyeicosatetraenoic acids) to their HETE (hydroxyeicosatetraenoic acid) derivatives. ApoD, apoD(M49-A) and apoD(M157-A) all catalysed the reduction of HpETEs to their corresponding HETEs. Amino acid analysis of HpETE-treated apoD revealed a loss of one third of the methionine residues accompanied by the formation of MetSO. Additional studies using apoD(M93-A) indicated that Met(93) was required for HpETE reduction. We also assessed the impact that apoD MetSO formation has on protein aggregation by Western blotting of HpETE-treated apoD and human brain samples. ApoD methionine oxidation was associated with formation of apoD aggregates that were also detected in the hippocampus of AD patients. In conclusion, conversion of HpETE into HETE is mediated by apoD Met(93), a process that may contribute to apoD antioxidant function.

Apolipoprotein D subcellular distribution pattern in neuronal cells during oxidative stress

“…The same phenomenon has been observed in several cellular models where it has been shown that some stress conditions activate Apo D expression and induce Apo D mRNA accumulation (Do Carmo et al, 2002;He et al, 2009). In this sense, Apo D has been suggested as a neuroprotective protein that may be part of an antioxidant defense system (Do Carmo et al, 2007;Ganfornina et al, 2008), playing an evolutionary and crucial role in response to oxidative stress with a beneficial function mediated by the control of peroxide lipids (He et al, 2009) or directly by intrinsic antioxidant properties (Bhatia et al, 2011;Kim et al, 2009;Oakley et al, 2012;Zhang et al, 2010). Do Carmo et al (2007), using immortalized astrocytes and a hepatic cell line, found that growth arrest and lipopolysaccharide, a proinflamatory agonist, cause a subcellular accumulation of Apo D protein in the cytoplasm that is followed by its displacement to the cellular extensions and nucleus, where they proposed that it may modulate transduction signal pathways and some nuclear processes.…”

Oxidised protein metabolism: recent insights

“…A very important study recently identified Apolipoprotein D (ApoD), an extracellular lipid-binding lipoprotein, as having a lysosomal membrane stabilising function (Pascua-Maestro et al, 2017). ApoD can reduce radical-propagating lipid hydroperoxides (Bhatia et al, 2012) and was shown to be endocytosed and to inhibit lysosomal lipid peroxidation in vitro (Pascua-Maestro et al, 2017). The authors suggested that ApoD could play an important role in the brain by protecting neurones against oxidative damage and could have important implications in neurodegenerative disorders (Pascua-Maestro et al, 2017).…”

Protection Against Ischemia/Reperfusion Injury by High-Density Lipoprotein and Its Components

“…ApoD is known to be upregulated in the brains of patients with Alzheimer disease, and apoD aggregates were detected in the hippocampus of patients with Alzheimer disease. 7 In other studies, it was shown that overexpression in mouse brain of human apoD prevented the increase in brain lipid peroxides after oxidant treatment and improved survival; the loss of apoD had the opposite effect. 9 ApoD is carried in the plasma mainly on HDLs.…”

“…7,8 Treatment of apoD with hydroperoxyeicosatetraenoic acids resulted in loss of one-third of the methionine residues in apoD and was accompanied by the formation of methionine sulfoxide and resulted in protein aggregation. ApoD is known to be upregulated in the brains of patients with Alzheimer disease, and apoD aggregates were detected in the hippocampus of patients with Alzheimer disease.…”

“…15 As noted, apoD in the brains of patients with Alzheimer disease seems to show similar changes of oxidation and aggregation. 7,9 Thus, there is emerging evidence that one role for HDL and its associated proteins and enzymes may be to provide protection against oxidative damage to tissues as well as to modulate the acute phase response.…”