CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease.

Caccamo, Antonella; Maldonado, Monica A; Bokov, Alex F; Majumder, Smita; Oddo, Salvatore

Caccamo, Antonella; Maldonado, Monica A; Bokov, Alex F; Majumder, Smita; Oddo, Salvatore.

Afiliación

Caccamo A; Department of Physiology, and Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX 78229, USA.

Proc Natl Acad Sci U S A ; 107(52): 22687-92, 2010 Dec 28.

Article en En | MEDLINE | ID: mdl-21149712

RESUMEN

Cognitive dysfunction and memory loss are common features of Alzheimer's disease (AD). Abnormalities in the expression profile of immediate early genes that play a critical role in memory formation, such as the cAMP-response element binding protein (CREB), have been reported in the brains of AD patients. Here we show that amyloid-ß (Aß) accumulation, which plays a primary role in the cognitive deficits of AD, interferes with CREB activity. We further show that restoring CREB function via brain viral delivery of the CREB-binding protein (CBP) improves learning and memory deficits in an animal model of AD. Notably, such improvements occur without changes in Aß and tau pathology, and instead are linked to an increased level of brain-derived neurotrophic factor. The resulting data suggest that Aß-induced learning and memory deficits are mediated by alterations in CREB function, based on the finding that restoring CREB activity by directly modulating CBP levels in the brains of adult mice is sufficient to ameliorate learning and memory. Therefore, increasing CBP expression in adult brains may be a valid therapeutic approach not only for AD, but also for various brain disorders characterized by alterations in immediate early genes, further supporting the concept that viral vector delivery may be a viable therapeutic approach in neurodegenerative diseases.

Asunto(s)

Enfermedad de Alzheimer/metabolismo; Factor Neurotrófico Derivado del Encéfalo/metabolismo; Proteína de Unión a CREB/metabolismo; Discapacidades para el Aprendizaje/metabolismo; Trastornos de la Memoria/metabolismo; Enfermedad de Alzheimer/fisiopatología; Enfermedad de Alzheimer/terapia; Péptidos beta-Amiloides/metabolismo; Precursor de Proteína beta-Amiloide/genética; Precursor de Proteína beta-Amiloide/metabolismo; Animales; Western Blotting; Encéfalo/metabolismo; Encéfalo/patología; Células CHO; Proteína de Unión a CREB/genética; Cricetinae; Cricetulus; Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo; Modelos Animales de Enfermedad; Técnicas de Transferencia de Gen; Terapia Genética/métodos; Humanos; Discapacidades para el Aprendizaje/fisiopatología; Discapacidades para el Aprendizaje/terapia; Lentivirus/genética; Trastornos de la Memoria/fisiopatología; Trastornos de la Memoria/terapia; Ratones; Ratones Endogámicos C57BL; Ratones Transgénicos; Neuronas/metabolismo; Fosforilación; Proteínas tau/metabolismo

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor Neurotrófico Derivado del Encéfalo / Proteína de Unión a CREB / Enfermedad de Alzheimer / Discapacidades para el Aprendizaje / Trastornos de la Memoria Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2010 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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