CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease
Open accessAbstract
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.
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pCREB levels are reduced in 3xTg mice at 6 months of age.
“pCREB levels are also reduced in 3xTg mice at 6 months of age (48).”
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- Authors
- Caccamo, A., Maldonado, M. A., Bokov, A. F., Majumder, S., & Oddo, S.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Department of Physiology,
- The University of Texas at San Antonio (US)
- Arizona State University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-12-13
- Volume
- 107
- Issue
- 52
- Pages
- 22687-22692
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3012497
- OpenAlex
- W2145976523
- Cited by
- 249
- References
- 7
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 14 · 2023: 15 · 2022: 10 · 2021: 12 · 2020: 23 · 2019: 16 · 2018: 16 · 2017: 10 · 2016: 25 · 2015: 10 · 2014: 22 · 2013: 27 · 2012: 21
- FWCI
- 13.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of California, San Diego
- University of California, Irvine
- National Institute on Aging (R00AG029729, R00-AG29729-4)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, CREB, CREB-binding protein, brain-derived neurotrophic factor, amyloid-beta, learning and memory impairment, immediate early genes, viral gene delivery, cognitive impairment, neurodegenerative disease treatment
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cricetulus, Disease Models, Animal, Cricetinae, Humans, Learning Disabilities, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Phosphorylation, Blotting, Western, Genetic Therapy, Lentivirus, Amyloid beta-Peptides, CHO Cells, Amyloid beta-Protein Precursor, tau Proteins, Cyclic AMP Response Element-Binding Protein, Gene Transfer Techniques, Brain-Derived Neurotrophic Factor, CREB-Binding Protein, Mice
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