Research article summary (published 16 May 2006):

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

Full Abstract

In this study, we investigated the molecular basis for the altered signal transduction associated with soluble amyloid beta-protein (Abeta) 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 Abeta1-42 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 Abeta1-42 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 Abeta 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 Abeta oligomer in the hippocampus and provide the rationale for symptomatic treatment of AD.

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Author information

Author/s: Chong, Young Hae (YH); Shin, Yoo Jeong (YJ); Lee, Eun Ok (EO); Kayed, Rakez (R); Glabe, Charles G (CG); Tenner, Andrea J (AJ);

Affiliation: Department of Microbiology, College of Medicine, Division of Molecular Biology and Neuroscience, Ewha Medical Research Institute, Ewha Womans University, Yangcheonku, Seoul, 158-710, Korea. younghae(-atsign-)ewha.ac.kr

Grants: NS35144 (Agency:NINDS NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: The Journal of biological chemistry (J Biol Chem), published in United States. (Language: eng)

Reference: 2006-Jul; vol 281 (issue 29) : pp 20315-25

Dates: Created 2006/07/17; Completed 2006/09/19; Revised 2007/11/14;

PMID: 16714296, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Alzheimer Disease - metabolism; pathology Amyloid beta-Protein - metabolism Animals Caspase 3 Caspases - metabolism Cell Death Enzyme Activation Hippocampus - cytology; enzymology; pathology; physiopathology Humans

Humans L-Lactate Dehydrogenase - analysis Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism Neurotoxins Organ Culture Techniques Protein Kinase Inhibitors - pharmacology Rats tau Proteins - metabolism

Associated Chemicals: Amyloid beta-Protein (0) ; Neurotoxins (0) ; Protein Kinase Inhibitors (0) ; tau Proteins (0) ; L-Lactate Dehydrogenase (EC 1.1.1.27) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.1.37) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.1.37) ; CASP3 protein, human (EC 3.4.22.-) ; Casp3 protein, rat (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Caspases (EC 3.4.22.-)

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