Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling
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Changes in hippocampal function seem critical for cognitive impairment in Alzheimer's disease (AD). Although there is eventual loss of synapses in both AD and animal models of AD, deficits in spatial memory and inhibition of long-term potentiation (LTP) precede morphological alterations in the models, suggesting earlier biochemical changes in the disease. In the studies reported here we demonstrate that amyloid beta-peptide (Abeta) treatment of cultured hippocampal neurons leads to the inactivation of protein kinase A (PKA) and persistence of its regulatory subunit PKAIIalpha. Consistent with this, CREB phosphorylation in response to glutamate is decreased, and the decrease is reversed by rolipram, a phosphodiesterase inhibitor that raises cAMP and leads to the dissociation of the PKA catalytic and regulatory subunits. It is likely that a similar mechanism underlies Alphabeta inhibition of LTP, because rolipram and forskolin, agents that enhance the cAMP-signaling pathway, can reverse this inhibition. This reversal is blocked by H89, an inhibitor of PKA. These observations suggest that Alphabeta acts directly on the pathways involved in the formation of late LTP and agents that enhance the cAMP/PKA/CREB-signaling pathway have potential for the treatment of AD.
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NMDA receptor down-regulation appears to explain why glutamate stimulation of the CREB pathway is impaired by oligomers.
“NMDA-R down-regulation appears to explain why glutamate stimulation of the CREB pathway is impaired by oligomers (Tong et al., 2001; Vitolo et al., 2002).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Vitolo et al., 2002
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- Authors
- Vitolo, O. V., Sant'Angelo, A., Costanzo, V., Battaglia, F., Arancio, O., & Shelanski, M.
- Affiliations
- New York University (US)
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain and Department of Genetics and Development, Columbia University, New York, NY 10032; and Nathan Kline Research Institute, New York University School of Medicine, New York, NY 10016
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2002-09-20
- Volume
- 99
- Issue
- 20
- Pages
- 13217-13221
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC130613
- OpenAlex
- W1970164987
- Cited by
- 534
- References
- 27
- Citations by year
- 2026: 19 · 2025: 18 · 2024: 14 · 2023: 22 · 2022: 17 · 2021: 23 · 2020: 22 · 2019: 29 · 2018: 17 · 2017: 30 · 2016: 17 · 2015: 35 · 2014: 29 · 2013: 29 · 2012: 22
- FWCI
- 8.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- amyloid-beta, Alzheimer's disease, protein kinase A, CREB phosphorylation, long-term potentiation, cAMP signaling, rolipram, forskolin, H89, PKA regulatory subunit, hippocampal neurons, spatial memory
- MeSH terms
- Cyclic AMP, Animals, Cells, Cultured, Electrophysiology, Hippocampus, Models, Biological, Neurons, Phosphorylation, Time Factors, Blotting, Western, Signal Transduction, Amyloid beta-Peptides, Rats, Sprague-Dawley, Cyclic AMP Response Element-Binding Protein, Long-Term Potentiation, Cyclic AMP-Dependent Protein Kinases, Rats
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