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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
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ABSTRACT

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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    • "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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