An apolipoprotein E-based therapeutic improves outcome and reduces Alzheimer’s disease pathology following closed head injury: Evidence of pharmacogenomic interaction
| Autor: | Lori Durham, Michael P. Vitek, Hana N. Dawson, Pingping Song, David S. Warner, Patrick Sullivan, Daniel T. Laskowitz, Haichen Wang |
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| Rok vydání: | 2007 |
| Předmět: |
Apolipoprotein E
Pathology medicine.medical_specialty Apolipoprotein E2 Transgene Apolipoprotein E3 Down-Regulation Mice Transgenic Plaque Amyloid Peptide Mice Apolipoproteins E Degenerative disease Alzheimer Disease Head Injuries Closed medicine Amyloid precursor protein Animals Humans Gliosis chemistry.chemical_classification Amyloid beta-Peptides Microglia biology business.industry General Neuroscience Brain medicine.disease Peptide Fragments Treatment Outcome medicine.anatomical_structure chemistry Closed head injury biology.protein Encephalitis lipids (amino acids peptides and proteins) Alzheimer's disease business |
| Zdroj: | Neuroscience. 144:1324-1333 |
| ISSN: | 0306-4522 |
| DOI: | 10.1016/j.neuroscience.2006.11.017 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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