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J. Biol. Chem., Vol. 278, Issue 30, 27971-27980, July 25, 2003

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Activation of the c-Jun N-terminal Kinase Signaling Cascade Mediates the Effect of Amyloid- on Long Term Potentiation and Cell Death in Hippocampus

A ROLE FOR INTERLEUKIN-1?^*

Aedín M. Minogue  , Adrian W. Schmid ¶, Marie P. Fogarty , Alison C. Moore , Veronica A. Campbell , Caroline E. Herron ¶ and Marina A. Lynch  ||

From the Trinity College Institute of Neuroscience, Department of Physiology, Trinity College, Dublin 2, Ireland and the ^¶Department of Human Anatomy and Physiology, Conway Institute, University College Dublin, Earlsfort Terrace, Dublin 2, Ireland

Amyloid- (A) is a major constituent of the neuritic plaque found in the brain of Alzheimer's disease patients, and a great deal of evidence suggests that the neuronal loss that is associated with the disease is a consequence of the actions of A. In the past few years, it has become apparent that activation of c-Jun N-terminal kinase (JNK) mediates some of the effects of A on cultured cells; in particular, the evidence suggests that A-triggered JNK activation leads to cell death. In this study, we investigated the effect of intracerebroventricular injection of A_(1–40) on signaling events in the hippocampus and on long term potentiation in Schaffer collateral CA1 pyramidal cell synapses in vivo. We report that A_(1–40) induced activation of JNK in CA1 and that this was coupled with expression of the proapoptotic protein, Bax, cytosolic cytochrome c, poly-(ADP-ribose) polymerase cleavage, and Fas ligand expression in the hippocampus. These data indicate that A_(1–40) inhibited expression of long term potentiation, and this effect was abrogated by administration of the JNK inhibitor peptide, D-JNKI1. In parallel with these findings, we observed that A-induced changes in caspase-3 activation and TdT-mediated dUTP nick-end labeling staining in neuronal cultured cells were inhibited by D-JNKI1. We present evidence suggesting that interleukin (IL)-1 plays a significant role in mediating the effects of A_(1–40) because A_(1–40) increased hippocampal IL-1 and because several effects of A_(1–40) were inhibited by the caspase-1 inhibitor Ac-YVAD-CMK. On the basis of our findings, we propose that A-induced changes in hippocampal plasticity are likely to be dependent upon IL-1-triggered activation of JNK.

Received for publication, March 12, 2003 , and in revised form, April 30, 2003.

^* This work was supported by grants from Enterprise Ireland, the Roche Research Foundation, and the Health Research Board, Ireland (to M. P. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a Trinity College Ussher Fellowship.

^|| To whom correspondence should be addressed. Tel.: 353-1-608-1770; Fax: 353-1-679-3545; E-mail: lynchma{at}tcd.ie.

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