Apolipoprotein D mRNA expression is elevated in PDAPP transgenic mice

Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 01/2002; 79(5):1059-64. DOI: 10.0000/096381898336501
Source: PubMed


Apolipoprotein D (apoD) expression is known to be elevated in select regions of rodent and human brain in association with different types of CNS pathology. To investigate a potential role for apoD in the neuropathology of Alzheimer's disease, we have measured apoD mRNA expression in transgenic mice expressing mutated human amyloid precursor protein under control of platelet-derived growth factor promoter (PDAPP mice). In situ hybridization analysis revealed increased apoD mRNA expression in brains of aged (26 months) PDAPP transgenic mice compared to aged littermate controls. These increases were most prominent in the hippocampal fimbria, corpus callosum and other white matter tracts. No substantial increases in expression were observed in white matter regions in young (6 months) PDAPP transgenic mice compared to young controls. Comparison between aged and young control mice revealed increased apoD expression in similar white matter regions of the aged animals. These findings suggest that, although increases in apoD expression are a normal feature of brain aging, super-increases may represent a glial cell compensatory response to beta-amyloid deposition in Alzheimer's disease.

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Available from: Elizabeth A Thomas, Nov 22, 2014
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    • "More recent studies have sown that loss of apoD in the APP/PS1 amyloidogenic Alzheimer's disease (AD) mouse model significantly worsens AD pathology, whereas neuronal expression of human apoD in the same AD mouse model reduces AD pathology [19]. These observations, along with the known induction of apoD in affected brain regions in human AD and mouse models20212223242526, underscore the importance of defining possible difference in apoD expression in different brain regions that may be susceptible to oxidative stress and neurodegenerative conditions. Previous studies have quantitatively assessed the expression of apoD mRNA levels in the brain and other tissues, and there are several reports demonstrating the presence of apoD protein in specific brain areas such as the hippocampus, cerebellum, dorsolateral pre-frontal cortex and substantia nigra. "
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    ABSTRACT: Recent studies have shown that cerebral apoD levels increase with age and in Alzheimer's disease (AD). In addition, loss of cerebral apoD in the mouse increases sensitivity to lipid peroxidation and accelerates AD pathology. Very little data are available, however, regarding the expression of apoD protein levels in different brain regions. This is important as both brain lipid peroxidation and neurodegeneration occur in a region-specific manner. Here we addressed this using western blotting of seven different regions (olfactory bulb, hippocampus, frontal cortex, striatum, cerebellum, thalamus and brain stem) of the mouse brain. Our data indicate that compared to most brain regions, the hippocampus is deficient in apoD. In comparison to other major organs and tissues (liver, spleen, kidney, adrenal gland, heart and skeletal muscle), brain apoD was approximately 10-fold higher (corrected for total protein levels). Our analysis also revealed that brain apoD was present at a lower apparent molecular weight than tissue and plasma apoD. Utilising peptide N-glycosidase-F and neuraminidase to remove N-glycans and sialic acids, respectively, we found that N-glycan composition (but not sialylation alone) were responsible for this reduction in molecular weight. We extended the studies to an analysis of human brain regions (hippocampus, frontal cortex, temporal cortex and cerebellum) where we found that the hippocampus had the lowest levels of apoD. We also confirmed that human brain apoD was present at a lower molecular weight than in plasma. In conclusion, we demonstrate apoD protein levels are variable across different brain regions, that apoD levels are much higher in the brain compared to other tissues and organs, and that cerebral apoD has a lower molecular weight than peripheral apoD; a phenomenon that is due to the N-glycan content of the protein.
    Full-text · Article · Feb 2016 · PLoS ONE
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    • "Specifically, ApoD has been demonstrated to be significantly upregulated in the brain of a transgenic mouse with an overexpressed highly amyloidogenic, that is, Aβ producing, form of human amyloid precursor protein. As is typical for AD, this effect was observed only in aged (26-month-old), but not young (6-month-old) animals (Thomas et al., 2001c). While these results do not necessarily imply a neuroprotective role for ApoD in AD, recent biochemical data do in fact suggest precisely such a role. "
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    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.
    Full-text · Article · Feb 2014 · Neurobiology of aging
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    • "ApoD is known to be induced in the brain not only during virus infections (Prosniak et al., 2001; Johnston et al., 2001) but also during several neuropathological conditions such as schizophrenia (Thomas et al., 2001a), Alzheimer's disease, (Thomas et al., 2001b) etc. It is considered to be an acute phase protein involved in the removal of lipids during nerve cell degeneration and provision of lipids during the regenerative phase (Reindl et al., 2001). "
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    ABSTRACT: This study identified nine genes whose expression is upregulated in the central nervous system (CNS) of mice during Japanese encephalitis virus (JEV) infection. These include: cathepsin S, oligoadenylate synthetase (OAS), GARG49/IRG2, lymphocyte antigen-6A (Ly-6A), macrophage activation gene-2 (Mpa2), early growth response gene1 (Egr1), pyrimidine 5'-nucleotidase (P5N), apolipoprotein D (ApoD) and STAT1. Activation of all nine genes during JEV infection was confirmed by Northern blot analysis. JEV replication was inhibited in the majority of mice immunized with Biken JEV vaccine, and these mice also exhibited reduced expression of JEV-inducible CNS genes. Thus, there is a good correlation between virus load and upregulation of host CNS genes. It was also demonstrated that all the CNS genes activated by JEV are also upregulated during rabies virus infection. In addition, GARG49, STAT1, cathepsin S and ApoD are known to be upregulated in the CNS by Sindbis virus, an alphavirus, and this supports the proposal that common host cell pathways are activated in the CNS by different neurotropic viruses.
    Full-text · Article · Aug 2003 · Journal of General Virology
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