Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCAI polymorphisms

Department of Neurology, Washington University, St, Louis, MO, USA.
Molecular Neurodegeneration (Impact Factor: 6.56). 04/2007; 2(1):7. DOI: 10.1186/1750-1326-2-7
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Animal studies suggest that brain apolipoprotein E (apoE) levels influence amyloid-β (Aβ) deposition and thus risk for Alzheimer's disease (AD). We have previously demonstrated that deletion of the ATP-binding cassette A1 transporter (ABCA1) in mice causes dramatic reductions in brain and cerebrospinal fluid (CSF) apoE levels and lipidation. To examine whether polymorphisms in ABCA1 affect CSF apoE levels in humans, we measured apoE in CSF taken from 168 subjects who were 43 to 91 years old and were either cognitively normal or who had mild AD. We then genotyped the subjects for ten previously identified ABCA1 single nucleotide polymorphisms (SNPs).
In all subjects, the mean CSF apoE level was 9.09 μg/ml with a standard deviation of 2.70 μg/ml. Levels of apoE in CSF samples taken from the same individual two weeks apart were strongly correlated (r2 = 0.93, p < 0.01). In contrast, CSF apoE levels in different individuals varied widely (coefficient of variation = 46%). CSF apoE levels did not vary according to AD status, APOE genotype, gender or race. Average apoE levels increased with age by ~0.5 μg/ml per 10 years (r2 = 0.05, p = 0.003). We found no significant associations between CSF apoE levels and the ten ABCA1 SNPs we genotyped. Moreover, in a separate sample of 1225 AD cases and 1431 controls, we found no association between the ABCA1 SNP rs2230806 and AD as has been previously reported.
We found that CSF apoE levels vary widely between individuals, but are stable within individuals over a two-week interval. AD status, APOE genotype, gender and race do not affect CSF apoE levels, but average CSF apoE levels increase with age. Given the lack of association between CSF apoE levels and genotypes for the ABCA1 SNPs we examined, either these SNPs do not affect ABCA1 function or if they do, they do not have strong effects in the CNS. Finally, we find no evidence for an association between the ABCA1 SNP rs2230806 and AD in a large sample set.

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    • "For example, the apoE:Aβ ratios reported for human CSF are in the range of 1:0.006-0.02 [72-74]. In addition, density gradient centrifugation is known to induce loss of (apolipo)proteins from lipoproteins [67], which would likely effect the components of the apoE/Aβ complex isolated by this method. "
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    ABSTRACT: The APOE4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer's disease (AD) compared to APOE2 and APOE3. Amyloid-beta (Abeta), particularly in a soluble oligomeric form (oAbeta), is considered a proximal cause of neurodegeneration in AD. Emerging data indicate that levels of soluble oAbeta are increased with APOE4, providing a potential mechanism of APOE4-induced AD risk. However, the pathway(s) by which apoE4 may increase oAbeta levels are unclear and the subject of continued inquiry. In this editorial review, we present the hypothesis that apoE isoform-specific interactions with Abeta, namely apoE/Abeta complex, modulate Abeta levels. Specifically, we propose that compared to apoE3, apoE4-containing lipoproteins are less lipidated, leading to less stable apoE4/Abeta complexes, resulting in reduced apoE4/Abeta levels and increased accumulation, particularly of oAbeta. Evidence that support or counter this argument, as well as the therapeutic significance of this pathway to neurodegeneration, are discussed.
    Molecular Neurodegeneration 01/2014; 9(1):2. DOI:10.1186/1750-1326-9-2 · 6.56 Impact Factor
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    • "With no added ApoE, there was no evidence of neuronal LNP uptake, whereas graded uptake was observed when ApoE concentrations were increased above 0.1μg/ml to 1 μg/ml and 5 µg/ml ApoE. The concentrations of ApoE found in the brain are similar to the concentrations we found to be effective in cell culture.16 This suggests that the natural affinity of these LNP systems for endogenous ApoE in the brain provides a highly efficient method for LNP delivery into neurons in vivo. "
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    ABSTRACT: Manipulation of gene expression in the brain is fundamental for understanding the function of proteins involved in neuronal processes. In this article, we show a method for using small interfering RNA (siRNA) in lipid nanoparticles (LNPs) to efficiently silence neuronal gene expression in cell culture and in the brain in vivo through intracranial injection. We show that neurons accumulate these LNPs in an apolipoprotein E-dependent fashion, resulting in very efficient uptake in cell culture (100%) with little apparent toxicity. In vivo, intracortical or intracerebroventricular (ICV) siRNA-LNP injections resulted in knockdown of target genes either in discrete regions around the injection site or in more widespread areas following ICV injections with no apparent toxicity or immune reactions from the LNPs. Effective targeted knockdown was demonstrated by showing that intracortical delivery of siRNA against GRIN1 (encoding GluN1 subunit of the NMDA receptor (NMDAR)) selectively reduced synaptic NMDAR currents in vivo as compared with synaptic AMPA receptor currents. Therefore, LNP delivery of siRNA rapidly manipulates expression of proteins involved in neuronal processes in vivo, possibly enabling the development of gene therapies for neurological disorders.Molecular Therapy-Nucleic Acids (2013) 2, e136; doi:10.1038/mtna.2013.65; published online 3 December 2013.
    Molecular Therapy - Nucleic Acids 12/2013; 2(12):e136. DOI:10.1038/mtna.2013.65 · 4.51 Impact Factor
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    • "A total of 14 studies have been conducted to investigate the association of ABCA1 gene polymorphisms with the risk for AD (Wollmer et al., 2003; Katzov et al., 2004; Li et al., 2004; Kolsch et al., 2006; Shibata et al., 2006; Chu et al., 2007; Rodriguez-Rodriguez et al., 2007, 2009, 2010; Sundar et al., 2007; Wahrle et al., 2007; Wang and Jia, 2007; Wavrant-De Vrieze et al., 2007; Reynolds et al., 2009). Eight of these studies link single nucleotide polymorphisms (SNP) in the ABCA1 gene to an increased risk for AD (Katzov et al., 2004; Shibata et al., 2006; Chu et al., 2007; Rodriguez-Rodriguez et al., 2007; Sundar et al., 2007; Wang and Jia, 2007; Wavrant-De Vrieze et al., 2007; Reynolds et al., 2009). "
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    ABSTRACT: Alzheimer's disease (AD) is considered the "disease of the twenty-first century." With a 10-fold increase in global incidence over the past 100 years, AD is now reaching epidemic proportions and by all projections, AD patient numbers will continue to rise. Despite intense research efforts, AD remains a mystery and effective therapies are still unavailable. This represents an unmet need resulting in clinical, social, and economic problems. Over the last decade, a new AD research focus has emerged: ATP-binding cassette (ABC) transporters. In this article, we provide an overview of the ABC transporters ABCA1, ABCA2, P-glycoprotein (ABCB1), MRP1 (ABCC1), and BCRP (ABCG2), all of which are expressed in the brain and have been implicated in AD. We summarize recent findings on the role of these five transporters in AD, and discuss their potential to serve as therapeutic targets.
    Frontiers in Psychiatry 06/2012; 3(45):54. DOI:10.3389/fpsyt.2012.00054
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