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J. Biol. Chem., Vol. 281, Issue 29, 20315-20325, July 21, 2006

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ERK1/2 Activation Mediates A Oligomer-induced Neurotoxicity via Caspase-3 Activation and Tau Cleavage in Rat Organotypic Hippocampal Slice Cultures^*

Young Hae Chong¹, Yoo Jeong Shin, Eun Ok Lee, Rakez Kayed, Charles G. Glabe, and Andrea J. Tenner

From the Department of Microbiology, College of Medicine, Division of Molecular Biology and Neuroscience, Ewha Medical Research Institute, Ewha Womans University, 911-1, Mok-6-dong, Yangcheonku, Seoul, 158-710, Korea and the Department of Molecular Biology and Biochemistry, Center for Immunology, University of California, Irvine, California 92697

In this study, we investigated the molecular basis for the altered signal transduction associated with soluble amyloid -protein (A) oligomer-mediated neurotoxicity in the hippocampus, which is primarily linked to cognitive dysfunction in Alzheimer disease (AD). As measured by media lactate dehydrogenase levels, and staining with propidium iodide, acute exposure to low micromolar concentrations of the A1-42 oligomer significantly induced cell death. This was accompanied by activation of the ERK1/2 signal transduction pathway in rat organotypic hippocampal slices. Notably, this resulted in caspase-3 activation by a process that led to proteolytic cleavage of Tau, which was recently confirmed to occur in AD brains. Tau cleavage likely occurred in the absence of overt synaptic loss, as suggested by the preserved levels of synaptophysin, a presynaptic marker. Moreover, among the pharmacological agents tested to inhibit several kinase cascades, only the ERK inhibitor significantly attenuated A1-42 oligomer-induced toxicity concomitant with the reduction of activation of ERK1/2 and caspase-3 to a lesser extent. Importantly, the caspase-3 inhibitor also decreased A oligomer-induced cell death, with no appreciable effect on the ERK signaling pathway, although such treatment was effective in reducing caspase-3 activation and Tau cleavage. Therefore, these results suggest that local targeting of the ERK1/2 signaling pathway to reduce Tau cleavage, as occurs with the inhibition of caspase-3 activation, may modulate the neurotoxic effects of soluble A oligomer in the hippocampus and provide the rationale for symptomatic treatment of AD.

Received for publication, February 2, 2006 , and in revised form, April 21, 2006.

^* This work was supported by Grant A040042 from the Biomedical Brain Research Center of the Korea Health 21 R&D Project funded by the Ministry of Health and Welfare, Republic of Korea (to Y. H. C.) and by National Institutes of Health Grant NS 35144 (to A. J. T.). 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.

¹ To whom correspondence should be addressed. Tel.: 822-02-2650-5739; Fax: 822-02-2653-8891; E-mail: younghae{at}ewha.ac.kr.

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