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

Abstract

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 A␤1-42 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 A␤1-42 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. Alzheimer disease (AD)2 neuropathology is characterized by key features that include fibrillar amyloid ␤-protein (A␤) deposition into dense senile plaques, the formation of neurofibrillary tangles composed of hyperphosphorylated Tau, and the loss of neurons and synapses in the affected brain region leading to the progressive loss of cognitive function (1, 2). Recent evidence suggests that soluble, prefibrillar, and oligomeric forms of A␤ are acutely toxic (3) and can interfere with synaptic plasticity in the brain, suggesting that this form of the peptide may be responsible for episodic memory deficits, an early symptom of AD, which is linked to hippocampal pathology (4). In fact, soluble A␤ oligomers, also referred as A␤-derived diffusible ligands, strikingly elevated in the AD brain (5-8) are also described in human amyloid precursor protein transgenic mice AD models (9) and can inhibit the long term potentiation (LTP) of synaptic efficiency (10, 11). The pathogenic relevance of this form of A␤ has been substantiated by a newly identified Arctic familial AD mutation, which has an increased propensity to oligomerize (12, 13), and by in vitro data demonstrating potent neurotoxicity upon exposure to soluble oligomer or protofibrils (3,14,15). Moreover, the ultrastructural localization of A␤ oligomer within neuritic processes and at synaptic terminals in AD brains (16,17) further supports...

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