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Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment
Open accessAbstract
Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid beta-peptide 1-42 (Abeta42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for amyloid precursor protein (AA substitution K670N,M671L) and presenilin-1 (AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Abeta. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Abeta42 levels.
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“Tg-mouse AD models manifest a spontaneous age-onset impairment of LTP (Gong et al., 2004) that presumably is linked to impaired performance in memory tests (Arendash et al., 2001).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Gong et al., 2004
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“Finally, since PDE4 inhibitors are being tested in clinical trials to treat common chronic diseases including Alzheimer’s disease (Gong et al., 2004), asthma, and COPD (Giembycz, 2002), it is important to understand the consequences of long-term inhibition of PDE4 activity in the heart, where PDE4 activity plays a maj…”
BackgroundThe Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease
Ferreira, S. T., & Klein, W. L. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.08.003 · Cited by 442
Metadata
- Authors
- Gong, B., Vitolo, O. V., Trinchese, F., Liu, S., Shelanski, M., & Arancio, O.
- Affiliations
- Nathan Kline Institute for Psychiatric Research (US)
- Columbia University (US)
- Venue
- Journal of Clinical Investigation
- Published
- 2004-12-01
- Volume
- 114
- Issue
- 11
- Pages
- 1624-1634
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC529285
- OpenAlex
- W2034986487
- Cited by
- 442
- References
- 60
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 16 · 2023: 15 · 2022: 11 · 2021: 13 · 2020: 21 · 2019: 20 · 2018: 17 · 2017: 33 · 2016: 17 · 2015: 20 · 2014: 28 · 2013: 23 · 2012: 23
- FWCI
- 12.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- University of Minnesota
- York University
- National Institutes of Health
- School of Medicine, New York University
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, rolipram, amyloid-beta 42, synaptic plasticity, long-term potentiation, contextual learning, memory impairment, phosphodiesterase-4 inhibitors, cAMP/PKA/CREB signaling, synaptic transmission, APP/PS1 double transgenic mice
- MeSH terms
- Alzheimer Disease, Animals, Cognition, Disease Models, Animal, Hippocampus, Humans, Learning, Male, Membrane Proteins, Mice, Transgenic, Synaptic Transmission, Phosphodiesterase Inhibitors, Amyloid beta-Protein Precursor, Cyclic AMP Response Element-Binding Protein, Long-Term Potentiation, Rolipram, Mice, Presenilin-1, In Vitro Techniques
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