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The Journal of Neuroscience, July 20, 2005, 25(29):6887-6897; doi:10.1523/JNEUROSCI.5291-04.2005

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Neurobiology of Disease
Amyloid- Peptide Inhibits Activation of the Nitric Oxide/cGMP/cAMP-Responsive Element-Binding Protein Pathway during Hippocampal Synaptic Plasticity

Daniela Puzzo,^1,3,5 Ottavio Vitolo,⁴ Fabrizio Trinchese,^1,3 Joel P. Jacob,^1,3 Agostino Palmeri,⁵ and Ottavio Arancio^1,2,3,4

¹Department of Psychiatry and ²Departments of Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016, ³Dementia Research Center, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962, ⁴Department of Pathology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York 10032, and ⁵Department of Physiological Sciences, University of Catania, 95125 Catania, Italy

Amyloid- (A), a peptide thought to play a crucial role in Alzheimer's disease (AD), has many targets that, in turn, activate different second-messenger cascades. Interestingly, A has been found to markedly impair hippocampal long-term potentiation (LTP). To identify a new pathway that might be responsible for such impairment, we analyzed the role of the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP/cGMP-dependent protein kinase (cGK)/cAMP-responsive element-binding protein (CREB) cascade because of its involvement in LTP. The use of the NO donor 2-(N,N-dethylamino)-diazenolate-2-oxide diethylammonium salt (DEA/NO), the sGC stimulator 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine, or the cGMP-analogs 8-bromo-cGMP and 8-(4-chlorophenylthio)-cGMP reversed the A-induced impairment of CA1-LTP through cGK activation. Furthermore, these compounds reestablished the enhancement of CREB phosphorylation occurring during LTP in slices exposed to A. We also found that A blocks the increase in cGMP immunoreactivity occurring immediately after LTP and that DEA/NO counteracts the effect of A. These results strongly suggest that, when modulating hippocampal synaptic plasticity, A downregulates the NO/cGMP/cGK/CREB pathway; thus, enhancement of the NO/cGMP signaling may provide a novel approach to the treatment of AD and other neurodegenerative diseases with elevated production of A.

Key words: Alzheimer's disease; amyloid-; hippocampus; long-term potentiation; synaptic plasticity; NO/cGMP/CREB pathway

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Received Dec 28, 2004; revised June 8, 2005; accepted June 8, 2005.

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