ERK1/2 activation mediates Abeta oligomer-induced neurotoxicity via caspase-3 activation and tau cleavage in rat organotypic hippocampal slice cultures.
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.
Chong
Young Hae
YH
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@ewha.ac.kr
Shin
Yoo Jeong
YJ
Lee
Eun Ok
EO
Kayed
Rakez
R
Glabe
Charles G
CG
Tenner
Andrea J
AJ
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D004789:Enzyme Activation; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009498:Neurotoxins; D009924:Organ Culture Techniques; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D047428:Protein Kinase Inhibitors; D016875:tau Proteins; D007770:L-Lactate Dehydrogenase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases