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

Wang, H; Durham, L; Dawson, H; Song, P; Warner, D S; Sullivan, P M; Vitek, M P; Laskowitz, D T

Wang, H; Durham, L; Dawson, H; Song, P; Warner, D S; Sullivan, P M; Vitek, M P; Laskowitz, D T.

Afiliación

Wang H; Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Durham, NC 27710, USA.

Neuroscience ; 144(4): 1324-33, 2007 Feb 23.

Article en En | MEDLINE | ID: mdl-17187933

RESUMEN

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.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico; Apolipoproteínas E/metabolismo; Encefalitis/tratamiento farmacológico; Traumatismos Cerrados de la Cabeza/tratamiento farmacológico; Fragmentos de Péptidos/farmacología; Enfermedad de Alzheimer/metabolismo; Enfermedad de Alzheimer/fisiopatología; Péptidos beta-Amiloides/efectos de los fármacos; Péptidos beta-Amiloides/metabolismo; Animales; Apolipoproteína E2/metabolismo; Apolipoproteína E3/metabolismo; Apolipoproteínas E/química; Apolipoproteínas E/genética; Encéfalo/efectos de los fármacos; Encéfalo/metabolismo; Encéfalo/fisiopatología; Regulación hacia Abajo/efectos de los fármacos; Regulación hacia Abajo/fisiología; Encefalitis/metabolismo; Encefalitis/fisiopatología; Gliosis/tratamiento farmacológico; Gliosis/fisiopatología; Gliosis/prevención & control; Traumatismos Cerrados de la Cabeza/metabolismo; Traumatismos Cerrados de la Cabeza/fisiopatología; Humanos; Ratones; Ratones Transgénicos; Microglía/efectos de los fármacos; Microglía/fisiología; Fragmentos de Péptidos/efectos de los fármacos; Fragmentos de Péptidos/metabolismo; Fragmentos de Péptidos/uso terapéutico; Placa Amiloide/efectos de los fármacos; Placa Amiloide/metabolismo; Resultado del Tratamiento

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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Apolipoproteínas E / Fragmentos de Péptidos / Traumatismos Cerrados de la Cabeza / Encefalitis / Enfermedad de Alzheimer Idioma: En Revista: Neuroscience Año: 2007 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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