ERK1/2 activation mediates Aβ oligomer-induced neurotoxicity via caspase-3 activation and Tau cleavage in rat organotypic hippocampal slice cultures

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

Research output: Contribution to journalArticle

146 Scopus citations

Abstract

In this study, we investigated the molecular basis for the altered signal transduction associated with soluble amyloid β-protein (Aβ) 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 Aβ1-42 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 Aβ1-42 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 Aβ 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 Aβ oligomer in the hippocampus and provide the rationale for symptomatic treatment of AD.

Original languageEnglish (US)
Pages (from-to)20315-20325
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number29
DOIs
StatePublished - Jul 21 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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