Calcium/calmodulin dependent protein kinase-II inhibition attenuates beta-amyloid induced neurotoxicity

Abstract

Beta-amyloid (A ) peptides induce neurotoxicity in Alzheimer's disease. Disruption of intracellular calcium homeostasis is one of the major causes. The exact mechanisms of intracellular calcium overload leading to neuronal apoptosis, however, is unclear. We suggest that calcium/calmodulin-dependent protein kinase II (CaMKII), an ubiquitous calcium-dependent kinases in the brain, mediates such kind of neurotoxicity . We used A peptides (A 25-35, A 1-42) treated rat primary cortical cells as a neurotoxicity model. By treating the neurons with three selective CaMKII inhibitors, namely, autocamtide-related inhibitory peptide (AIP), KN93 and KN62, we found that the A peptides mediated neurotoxicity was significantly reduced. General neurotoxicity as reflected from the LDH levels were significantly decreased with the treatments of AIP, KN93 and KN62 by 44%, 22% and 26% respectively. Moreover, all inhibitors significantly attenuated A peptide-induced caspase 2 activation by 36%, 19% and 17%, respectively. The caspase 3 activities were also reduced by 35%, 19% and 17% in respective group. In addition, all three CaMKII inhibitors significantly decreased the degree of DNA fragmentation/condensation (by DAPI staining) in the A peptide-intoxicated neurons. Tau hyperphosphorylation of the A peptide-treated neurons were also significantly reduced by the treatment with the CaMKII inhibitors. W7 (Non-selective calmodulin antagonist) and KN92 (inactive structural analogue of KN93) did not provide neuroprotection. The results suggest that CaMKII plays a role in A -induced neurotoxicity. Therefore, CaMKII may be a potential target of therapeutic agents against Alzheimer's disease.