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Research Article

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

Antonella Caccamo, Monica A. Maldonado, Alex F. Bokov, Smita Majumder, and Salvatore Oddo
  1. aDepartment of Physiology,
  2. bBarshop Institute for Longevity and Aging Studies, and
  3. cDepartment of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX 78229

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PNAS first published December 13, 2010; https://doi.org/10.1073/pnas.1012851108
Antonella Caccamo
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Monica A. Maldonado
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Alex F. Bokov
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Smita Majumder
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Salvatore Oddo
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  • For correspondence: oddo@uthscsa.edu
  1. Edited by James L. McGaugh, University of California, Irvine, CA, and approved November 17, 2010 (received for review August 30, 2010)

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Abstract

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-β (Aβ) 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 Aβ and tau pathology, and instead are linked to an increased level of brain-derived neurotrophic factor. The resulting data suggest that Aβ-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.

  • tangles
  • presenilin

Footnotes

  • 1To whom correspondence should be addressed. E-mail: oddo{at}uthscsa.edu.
  • Author contributions: S.O. designed research; A.C., M.A.M., S.M., and S.O. performed research; A.C., A.F.B., and S.O. analyzed data; and S.O. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1012851108/-/DCSupplemental.

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CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease
Antonella Caccamo, Monica A. Maldonado, Alex F. Bokov, Smita Majumder, Salvatore Oddo
Proceedings of the National Academy of Sciences Dec 2010, 201012851; DOI: 10.1073/pnas.1012851108

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CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease
Antonella Caccamo, Monica A. Maldonado, Alex F. Bokov, Smita Majumder, Salvatore Oddo
Proceedings of the National Academy of Sciences Dec 2010, 201012851; DOI: 10.1073/pnas.1012851108
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