An apolipoprotein E-based therapeutic improves outcome and reduces Alzheimer’s disease pathology following closed head injury: Evidence of pharmacogenomic interaction

Department of Anesthesiology, Duke University, Durham, North Carolina, United States
Neuroscience (Impact Factor: 3.36). 03/2007; 144(4):1324-33. DOI: 10.1016/j.neuroscience.2006.11.017
Source: PubMed


Apolipoprotein E (apoE) modifies glial activation and the CNS inflammatory response in an isoform-specific manner. Peptides derived from the receptor-binding region of apoE have been demonstrated to maintain the functional activity of the intact protein, and to improve histological and functional deficits after closed head injury. In the current study, APOE2, APOE3, and APOE4 targeted replacement (TR) mice expressing the human apoE protein isoforms (apoE2, apoE3 and apoE4) were used in a clinically relevant model of closed head injury to assess the interaction between the humanized apoE background and the therapeutic apoE mimetic peptide, apoE(133-149). Treatment with the apoE-mimetic peptide reduced microglial activation and early inflammatory events in all of the targeted replacement animals and was associated with histological and functional improvement in the APOE2TR and APOE3TR animals. Similarly, brain beta amyloid protein (Abeta)(1-42) levels were increased as a function of head injury in all of the targeted replacement mice, while treatment with apoE peptide suppressed Abeta(1-42) levels in the APOE2TR and APOE3TR animals. These results suggest a pharmacogenomic interaction between the therapeutic effects of the apoE mimetic peptide and the human apoE protein isoforms. Furthermore, they suggest that administration of apoE-mimetic peptides may serve as a novel therapeutic strategy for the treatment of acute and chronic neurological disease.

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    • "Recently, a novel apolipoprotein E (ApoE) COG 133 mimetic peptide, comprising residues 133–149 of the human apolipoprotein E has been reported [8]. This mimetic peptide competes with the ApoE holoprotein for binding the LDL receptor, with potent anti-inflammatory properties in models of brain injury, yet preserving the neuroprotective role of the holoprotein [9,10]. "
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    ABSTRACT: Intestinal mucositis is one of the major troublesome side effects of anticancer chemotherapy leading to poor patient compliance. In this study we addressed the role of the novel apolipoprotein E (ApoE) COG 133 mimetic peptide in 5-fluorouracil (5-FU)-challenged Swiss mice and IEC-6 cell monolayers. Experiments were also conducted in C57BL6J ApoE knock-out mice to assess the effects of apoE peptide treatment. Experimental groups were as follows: unchallenged controls, 5-FU-challenged mice (450 mg/kg, i.p) with or without the ApoE peptide (0.3, 1, and 3 μM, given twice daily i.p. for 4 days). Mice were sacrificed 3 days after 5-FU challenge. Proximal small intestinal samples were harvested for molecular biology and histological processing. We conducted ELISA assays and RT-PCR to target IL-1β, TNF-α, IL-10, iNOS, and myeloperoxidase (MPO) to assess intestinal inflammation. Cell death and NF-κB assays were also conducted in apoE knock-out mice. In our in vitro models, IEC-6 cells were exposed to 1 mM of 5-FU in glutamine free media with or without the ApoE peptide (0.02, 0.2, 2, 5, 10, and 20 μM). We investigated IEC-6 cell proliferation and migration, 24 h after the 5-FU challenge. Additionally, apoptotic IEC-6 cells were measured by Tunel and flow cytometry. Equimolar doses of the ApoA-I (D4-F) peptide were also used in some experiments for comparative studies. Villus blunting and heavy inflammatory infiltrates were seen in the 5-FU-challenged group, findings that were partially ameliorated by the ApoE peptide. We found increased intestinal MPO and pro-inflammatory IL-1β and TNF-α levels, and TNF-α and iNOS transcripts, and reduction of IL-10 following 5-FU treatment, each of which were partially abrogated by the peptide. Improvements were also found in IEC-6 cell apoptosis and migration following ApoE and D-4F treatment. Altogether, these findings suggest that the novel ApoE COG 133 mimetic peptide can reduce 5-FU-induced intestinal changes and potentially benefit mucositis.
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    • "In contrast, both apoE and βARs are thought to play important roles in neuroprotection afforded by astrocytes (Junker et al., 2002; Laureys et al., 2010; Rebeck et al., 2002). There is increasing evidence that apoE mimetics are neuroprotective in models of AD and neuronal injury (Christensen et al., 2011; Li, et al., 2010b; Wang et al., 2007). Aβ directly binds to the β 2 AR (Wang et al., 2010) and the β 2 AR is upregulated after brain injury (Cleary et al., 1995; Hodges-Savola et al., 1996; Junker et al., 2002). "
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    • "In the brain, predominantly in glial cells, apoE is secreted as unique high-density lipoprotein like particles (Fryer et al., 2005). It has three common isoforms (apoE2, E3, E4) encoded by three alleles (Orihara and Nakasono, 2002; Wang et al., 2007). The levels of apoE protein are maintained constant in adult and old mice brain cortex (Sarika and Thakur, 2010). "
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