Original articleApolipoprotein D levels are elevated in prefrontal cortex of subjects with Alzheimer’s disease: no relation to apolipoprotein E expression or genotype
Introduction
Alzheimer’s disease (AD) is a genetically complex, neurodegenerative disorder characterized primarily by global deficits in cognition, including loss of memory and impairment of judgment and reasoning. Hallmark pathologic features of AD include senile plaques, neurofibrillary tangles, and neuronal loss, and these occur primarily in the cerebral cortical areas and hippocampus. The entorhinal cortex, temporal cortex, and hippocampus are the first to accumulate neurofibrillary tangles, whereas lesions in the prefrontal cortex, a region of primary interest owing to its involvement in cognitive function, are not observed until later in the disease Bouras et al 1993, Braak and Braak 1995, Braak et al 1998, Hof et al 1995. These clinical and pathologic features are observed in both early- and late-onset forms of AD. Early-onset, familial AD (EOAD) cases can be caused by mutations in one of three known genes encoding the amyloid precursor protein, presenilin 1 and presenilin 2, which together account for half of all affected families (Tanzi and Bertram 2001). In the more common, late-onset form (LOAD), a polymorphism in the apolipoprotein E (APOE, gene; apoE, protein) gene has been associated with increased susceptibility (for a review, see Tomiyama et al 1999).
ApoE is one of a large family of apolipoproteins that are associated with lipoprotein complexes and are involved in lipid transport in various cell types and tissues. In humans, three major allelic variations in the APOE gene (ε2, ε3, and ε4) exist, which encode three protein isoforms that differ in their biological properties (Zannis et al 1981). Inheritance of the ε4 allele is a risk factor for developing late-onset familial and sporadic AD (sporadic cases have no known etiology) Corder et al 1993, Poirier et al 1993, Rebeck et al 1993, Strittmatter et al 1993. In addition to the genotyping studies, apoE messenger ribonucleic acid (mRNA) and protein levels have been shown to be elevated in brains of Alzheimer’s subjects Laws et al 2002, Yamada et al 1995, Yamagata et al 2001, and apoE immunoreactivity has been localized not only to the senile plaques but also to vascular amyloid and the neurofibrillary tangles of AD Harr et al 1996, Poirier 2000, Tomiyama et al 1999.
ApoD, although it is a component of high-density lipoprotein complexes, is a member of the lipocalin superfamily of lipid transport proteins. It has been previously associated with AD; however, its role is unclear. Increased apoD mRNA and/or protein expression has been detected in the cerebrospinal fluid (CSF), hippocampus, and selected cortical cell populations of AD subjects Belloir et al 2001, Kalman et al 2000, Terrisse et al 1998 and in the brains of an Alzheimer’s transgenic mouse model (PDAPP transgenic mice; these mice over-express the human amyloid precursor protein under the control of the platelet-derived growth factor promoter) (Thomas et al 2001b); however, unlike other apolipoproteins, such as apoE, apoA-1, apoJ, and apoB, the cortical senile plaques and neurofibrillary tangles observed in AD are immunonegative for apoD Belloir et al 2001, Calero et al 2000, Harr et al 1996, Kalman et al 2000, Namba et al 1991. We have previously demonstrated that apoD protein expression is elevated in prefrontal cortex and other select regions from subjects with schizophrenia and bipolar disorder, and we have suggested that elevated apoD levels may be useful as a marker for pathology associated with psychiatric disorders Thomas et al 2001a, Thomas et al 2002. Because cognitive impairment is one of the most important clinical features of AD, we investigated whether apoD levels were altered in the prefrontal cortex of subjects with AD.
Section snippets
Tissue collection and preparation
Frontal cortex tissue was obtained from 60 brain specimens collected from institutes in Perth (Hollywood Private Hospital [HPH]), Melbourne (University of Melbourne and the Mental Health Research Institute [MHRI]), Sydney (New South Wales Tissue Resource Center and The Neuroscience Institute of Schizophrenia and Allied Disorders [NISAD]) and Philadelphia (MCP-Hahnemann University). Alzheimer’s disease cases were neuropathologically confirmed based on established National Institute of
Results
In previous studies, we detected an increase in protein levels of apoE in the prefrontal cortex (Brodmann’s area 9) of subjects with Alzheimer’s disease (Laws et al 2002). This cohort consisted of subjects with EOAD and LOAD. In the present study, we have measured apoD protein levels in the same cohort using an ELISA. Levels of apoD expression in the AD subjects were significantly increased over those in the control subjects (.218 ± .029 μg/mg protein vs. .117 ± .011 μg/mg protein; p = .0003) (
Discussion
A growing number of studies have demonstrated increases in apoD expression in a variety of human neurologic diseases. In the present study, we observed an increase in apoD protein levels in prefrontal cortex of subjects with AD. These findings are in agreement with previous studies that have shown increased apoD expression in other regions of the brain in AD subjects. Increased mRNA and/or protein expression has been observed in the CSF and hippocampus of AD subjects (Terrisse et al 1998) and
Acknowledgements
This work was supported by the McCusker Foundation for Alzheimer’s Disease Research, National Institutes of Health Grants AG10491 (SEG), GM32355 (JGS), and NS44169 (EAT), and Digital Gene Technologies. SML is a recipient of a Dora Lush (Biomedical) postgraduate research scholarship from the National Health and Medical Research Council (NHMRC) (Australia).
Elizabeth A. Thomas and Simon M. Laws contributed equally to this article.
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