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PNAS 99 (20): 13217-13221

Copyright © 2002 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / NEUROSCIENCE

Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling

Ottavio V. Vitolo*,{dagger}, Antonino Sant'Angelo{dagger},{ddagger}, Vincenzo Costanzo§, Fortunato Battaglia{ddagger}, Ottavio Arancio{dagger},{ddagger}, and Michael Shelanski*,{dagger},¶

*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 {ddagger}Nathan Kline Research Institute, New York University School of Medicine, New York, NY 10016

Accepted for publication August 20, 2002.

Received for publication May 18, 2002.

Abstract: 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 β-peptide (Aβ) treatment of cultured hippocampal neurons leads to the inactivation of protein kinase A (PKA) and persistence of its regulatory subunit PKAIIα. 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 Aβ 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 Aβ 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.

{dagger} O.V.V., A.S.A., O.A., and M.S. contributed equally to this work.

To whom reprint requests should be addressed at: Department of Pathology, Columbia University, 630 West 168th Street, New York, NY 10032. E-mail: mls7{at}columbia.edu.

Communicated by Gerald D. Fischbach, Columbia University College of Physicians and Surgeons, New York, NY

|| Vitolo, O. V., Angelastro, J. M., Greene, L. A. & Shelanski, M. L. (2001) Am. Soc. Cell Biol. Meeting Abstract, 2063 (abstr.).

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