Apolipoprotein D takes center stage in the stress response of the aging and degenerative brain - PubMed (original) (raw)

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Apolipoprotein D takes center stage in the stress response of the aging and degenerative brain

Sarah Dassati et al. Neurobiol Aging. 2014 Jul.

Abstract

Apolipoprotein D (ApoD) is an ancient member of the lipocalin family with a high degree of sequence conservation from insects to mammals. It is not structurally related to other major apolipoproteins and has been known as a small, soluble carrier protein of lipophilic molecules that is mostly expressed in neurons and glial cells within the central and peripheral nervous system. Recent data indicate that ApoD not only supplies cells with lipophilic molecules, but also controls the fate of these ligands by modulating their stability and oxidation status. Of particular interest is the binding of ApoD to arachidonic acid and its derivatives, which play a central role in healthy brain function. ApoD has been shown to act as a catalyst in the reduction of peroxidized eicosanoids and to attenuate lipid peroxidation in the brain. Manipulating its expression level in fruit flies and mice has demonstrated that ApoD has a favorable effect on both stress resistance and life span. The APOD gene is the gene that is upregulated the most in the aging human brain. Furthermore, ApoD levels in the nervous system are elevated in a large number of neurologic disorders including Alzheimer's disease, schizophrenia, and stroke. There is increasing evidence for a prominent neuroprotective role of ApoD because of its antioxidant and anti-inflammatory activity. ApoD emerges as an evolutionarily conserved anti-stress protein that is induced by oxidative stress and inflammation and may prove to be an effective therapeutic agent against a variety of neuropathologies, and even against aging.

Keywords: Aging; Alzheimer's disease; Apolipoprotein; Inflammation; Lipid peroxidation; Lipocalin; Neurodegeneration; Oxidative stress; Reactive oxygen species; Schizophrenia; Stress response; Stroke.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

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Figures

Fig. 1

Fig. 1

ApoD is a lipocalin that has been evolutionarily conserved from insects to mammals. The secondary structure and sequence elements of human ApoD are compared with those of the Drosophila Lazarillo proteins, GLaz, and NLaz. The backbone of all 3 proteins is comprised of 8 beta sheets (arrows) that give rise to a barrel-like shape, which constitutes the ligand-binding pocket and is characteristic for lipocalins. This fold is stabilized by 4 conserved cysteine residues forming 2 disulfide bridges. All 3 orthologs have a signal peptide at their N-terminus (not shown) and a short alpha helix at the C-terminus (cylinder). While the highest sequence conservation is found in the beta sheets, the sequence stretches in between often contain hydrophobic residues which in human ApoD were shown to be organized as protruding loops framing the entrance to the binding pocket (Eichinger et al., 2007). These hydrophobic loops (blue) are assumed to be involved in defining the ligand specificity and also to facilitate the interaction of ApoD and Lazarillo proteins with hydrophobic surfaces. Lazarillo proteins in fact associate with membranes through a GPI-anchor (yellow bars), whereas human ApoD, but not the ApoD orthologs of other species, was found to be covalently linked to ApoA2 through a disulfide bridge. Met93 in human ApoD has been shown to have reducing activity and to prevent peroxidation of lipids. This methionine residue seems to be restricted to ApoD orthologs in higher vertebrates (mammals and birds). Abbreviation: ApoD, apolipoprotein D.

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