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: 3.33). 03/2007; 144(4):1324-33. DOI: 10.1016/j.neuroscience.2006.11.017
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer disease (AD) is the most common neurodegenerative disease affecting millions of patients worldwide. According to the amyloid cascade hypothesis, the formation of neurotoxic oligomers composed of amyloid-β (Aβ) peptides is the main mechanism that causes synaptic dysfunction and, eventually, neuronal cell death in this condition. Intriguingly, apolipoprotein E (apoE), the most important genetic risk factor for sporadic AD, emerges as a key factor that contributes to many aspects of the amyloid cascade including the clearance of Aβ from brain interstitial fluid and the ability of this peptide to form neurotoxic oligomers. Central to the activity of apoE in the healthy and in the diseased brain are apoE receptors that interact with this protein to mediate its multiple cellular and systemic effects. This review describes the molecular interactions that link apoE and its cellular receptors with neuronal viability and function, and how defects in these pathways in the brain promote neurodegeneration. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
    Wiley Interdisciplinary Reviews Systems Biology and Medicine 05/2014; 6(3). DOI:10.1002/wsbm.1262 · 3.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Chemotherapy-induced alimentary mucositis is an extremely common condition that is caused by a breakdown of the mucosal barrier. It occurs in between 40 - 100% of cancer patients depending on the treatment regimen. Symptoms typically include pain from oral ulceration, vomiting and diarrhoea. Alimentary mucositis often necessitates chemotherapy reductions or treatment breaks, overall potentially compromising survival outcomes. Consequently, alimentary mucositis creates a burden not only on patients' quality of life but also on healthcare costs. Despite this, currently, there is no clinically effective localised/pharmacological therapy intervention strategy to prevent alimentary mucositis. Areas covered: Over recent years, a number of novel pharmacotherapy agents have been trialed in various preclinical and clinical settings. This critical review will therefore provide an overview of emerging pharmacotherapies for the treatment of alimentary mucositis following chemotherapy with particular emphasis on studies published in the last 2 years. A Pubmed literature search was conducted to identify eligible articles published before 30 November 2013 and each article was reviewed by all authors. All articles were written in English. Expert opinion: Currently, there is no clinically effective localised therapeutic intervention strategy to prevent the condition. New emerging areas of research have recently been proposed to play key roles in the development of alimentary mucositis and these areas may provide researchers and clinicians with new research directions. Hopefully this will continue, and evidence-based informed guidelines can be produced to improve clinical practice management of this condition.
    Expert opinion on biological therapy 01/2014; DOI:10.1517/14712598.2014.874412 · 3.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite intensive research, neurological morbidity from delayed cerebral ischemia remains common after aneurysmal subarachnoid hemorrhage (SAH). In the current study, we evaluate the neuroprotective effects of a pH-dependent GluN2B subunit-selective NMDA receptor antagonist in a murine model of SAH. Following induction of SAH, 12 ± 2 week old male C57-BL/6 mice received NP10075, a pH-dependent NMDA receptor antagonist, or vehicle. In a separate series of experiments, NP10075 and the non-pH sensitive NMDA antagonist, NP10191, were administered to normoglycemic and hyperglycemic mice. Both histological (right middle cerebral artery diameter, NeuN, and Fluoro-Jade B staining) and functional endpoints (rotarod latency and neuroseverity score) were evaluated to assess the therapeutic benefit of NP10075. Administration of NP10075 was well tolerated and had minimal hemodynamic effects following SAH. Administration of the pH-sensitive NMDA antagonist NP10075, but not NP10191, was associated with a durable improvement in the functional performance of both normoglycemic and hyperglycemic animals. NP10075 was also associated with a reduction in vasospasm in the middle cerebral artery associated with hemorrhage. There was no significant difference between treatment with nimodipine + NP10075, as compared to NP10075 alone. These data demonstrate that use of a pH-dependent NMDA antagonist has the potential to work selectively in areas of ischemia known to undergo acidic pH shifts, and thus may be associated with selective regional efficacy and fewer behavioral side effects than non-selective NMDA antagonists.
    Neurocritical Care 01/2014; DOI:10.1007/s12028-013-9944-9 · 2.60 Impact Factor

Full-text (2 Sources)

Available from
Jun 6, 2014