Cited by 452Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchDementia and Cognitive Impairment Research

Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment

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Gong, Bing, Vitolo, Ottavio V., Trinchese, Fabrizio, Liu, Shumin, Shelanski, Michael, Arancio, Ottavio·2004·Journal of Clinical Investigation

Abstract

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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  • Transgenic mouse AD models manifest a spontaneous age-onset impairment of LTP that presumably is linked to impaired performance in memory tests.

    “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).”

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  1. Barad, M., Bourtchouladze, R., Winder, D.G., Golan, H., and Kandel, E. 1998. Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term poten- tiation and improves memory. Proc. Natl. Acad. Sci.

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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)
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
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
  • Health Sciences › Medicine › Physiology › 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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