Modulation of calcium/calmodulin kinase-II provides partial neuroprotection against beta-amyloid peptide toxicity

Abstract

Beta-amyloid (Aβ) peptide-induced neurotoxicity has been implicated in the pathogenesls of Alzheimer's disease (AD). The exact mechanism by which Aβ peptides trigger neuronal death is not well defined and may be related to an abrupt increase in intracellular calcium, leading to the activation of many pro-apoptotic pathways. While modulation of intracellular calcium increase receives much attention for pharmaceutical intervention, Ca2+- mediated pro-apoptotic signalling pathways have not been systematically studied. We have reported our study on the roles of calcium/calmodulin-dependent protein kinase II (CaMKII) in Aβ peptide neurotoxicity. By treating the primary cortical neurons exposed to Aβ peptides (Aβ25-35 and Aβ1-42) with two selective CaMKII inhibitors, autocamtide-related inhibitory peptide (AIP) and KN93, Aβ peptide neurotoxicity was significantly reduced. Release of LDH and DNA fragmentation/ condensation (by DAPI staining) in neurons exposed to Aβ peptides were significantly decreased in the presence of AIP and KN93. While these inhibitors significantly attenuated Aβ peptide-triggered activation of caspase-2 and caspase-3, and AIP significantly decreased the degree of tau phosphorylation of the Aβ peptide-treated neurons at early time, they could elicit partial neuroprotection only. Pharmacological inhibitor targeting calmodulin, W7, did not provide neuroprotection. Morphine, which activates CaMKII via μ receptors, augments Aβ-induced LDH release, caspase-2 and caspase-3 activities and neuronal apoptosis. Taken together, although CaMKII plays a role in Aβ peptide neurotoxicity, pharmacological inhibition cannot afford complete neuroprotection.