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

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.

Aging without Apolipoprotein D: Molecular and cellular modifications in the hippocampus and cortex

“…Among the genes regulated by age, the Lipocalin Apolipoprotein D (ApoD) has been reported, by genomic profiling analyses and a subsequent bioinformatic meta-analysis (de Magalhaes et al, 2009), to show the most consistent up-regulated expression in primates and rodents. This transcriptional regulation agrees with a number of widely known correlational studies showing high expression levels of ApoD in many aged model organisms, as well as in humans and rodents suffering from neurodegenerative conditions (reviewed by Dassati et al, 2014;Rassart et al, 2000). In this context, a recent report links ApoD expression levels to the regulation of amyloid plaque pathology in a mouse model of AD (Li et al, 2015).…”

“…Although ApoD expression has been reported to increase with age in many model organisms and humans (reviewed by Dassati et al, 2014), and ApoD homologues in Drosophila, GLaz and NLaz, show life extension phenotypes (Hull-Thompson et al, 2009;Ruiz et al, 2011;Sanchez et al, 2006;Walker et al, 2006), the absence of ApoD in mice results in a life expectancy similar to that of WT littermates (Fig. 1A) independently of the sex studied (combined sexes are shown in the figure).…”

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

“…Clusterin (ApoJ) polymorphism is associated with AD (Lambert et al ., 2009), and its circulating levels predict AD progression (Thambisetty et al ., 2010). Other apolipoproteins are also strongly linked to AD risk: ApoD catalyzes reduction of peroxidized lipids and its levels increase with age and AD, while ApoE has allele‐specific effects on Aβ levels and AD risk (Tai et al ., 2013; Dassati et al ., 2014). …”

Apolipoprotein D modulates amyloid pathology in APP/PS1 Alzheimer's disease mice

“…Interestingly, apoD dimers have been identified in the hippocampus, but not in the pathologically spared cerebellum, of human AD subjects (Bhatia et al, 2013). There is now a growing consensus that apoD may play a protective role in AD, and other neurological diseases (Bhatia et al, 2013;Dassati et al, 2014).…”