Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling
| Autor: | Antonino Sant'Angelo, Michael L. Shelanski, Ottavio Arancio, Fortunato Battaglia, Ottavio V. Vitolo, Vincenzo Costanzo |
|---|---|
| Přispěvatelé: | O. V., Vitolo, A., Sant'Angelo, Costanzo, Vincenzo, F., Battaglia, O., Arancio, M., Shelanski |
| Rok vydání: | 2002 |
| Předmět: |
medicine.medical_specialty
Time Factors Amyloid beta-Peptide Blotting Western Long-Term Potentiation metabolism Cyclic AMP Hippocampal formation CREB Hippocampus Models Biological metabolism Cyclic AMP-Dependent Protein Kinase Rats Sprague-Dawley chemistry.chemical_compound cytology Long-Term Potentiation Model Internal medicine Cyclic AMP medicine Animals Phosphorylation Phosphodiesterase inhibitor Cyclic AMP Response Element-Binding Protein Protein kinase A metabolism Electrophysiology Hippocampu Cells Cultured Rolipram Neurons Biological Neuron Sprague-Dawley Signal Transduction Time Factors Amyloid beta-Peptides Multidisciplinary Forskolin biology metabolism Phosphorylation Rats Rat Cultured Cyclic AMP Response Element-Binding Protein Glutamate receptor Long-term potentiation Biological Sciences pharmacology Animals Blotting Cyclic AMP-Dependent Protein Kinases Rats Cell biology Electrophysiology Endocrinology chemistry Western Cell biology.protein Signal Transduction medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 99:13217-13221 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.172504199 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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