Loss in PKC Epsilon Causes Downregulation of MnSOD and BDNF Expression in Neurons of Alzheimer's Disease Hippocampus

Oxidative stress and amyloid-beta (A beta) oligomers have been implicated in Alzheimer's disease (AD). The growth and maintenance of neuronal networks are influenced by brain derived neurotrophic factor (BDNF) expression, which is promoted by protein kinase C epsilon (PKC epsilon). We investigated the reciprocal interaction among oxidative stress, A beta, and PKC epsilon levels and subsequent PKC epsilon-dependent MnSOD and BDNF expression in hippocampal pyramidal neurons. Reduced levels of PKC epsilon, MnSOD, and BDNF and an increased level of A beta were also found in hippocampal neurons from autopsy-confirmed AD patients. In cultured human primary hippocampal neurons, spherical aggregation of A beta (amylospheroids) decreased PKC epsilon and MnSOD. Treatment with t-butyl hydroperoxide (TBHP) increased superoxide, the oxidative DNA/RNA damage marker, 8-OHG, and A beta levels, but reduced PKC epsilon, MnSOD, BDNF, and cultured neuron density. These changes were reversed with the PKC epsilon activators, bryostatin and DCPLA-ME. PKC epsilon knockdown suppressed PKC epsilon, MnSOD, and BDNF but increased A beta. In cultured neurons, the increase in reactive oxygen species (ROS) associated with reduced PKC epsilon during neurodegeneration was inhibited by the SOD mimetic MnTMPyP and the ROS scavenger NAc, indicating that strong oxidative stress suppresses PKC epsilon level. Reduction of PKC epsilon and MnSOD was prevented with the PKC epsilon activator bryostatin in 5-6-month-old Tg2576 AD transgenic mice. In conclusion, oxidative stress and A beta decrease PKC epsilon expression. Reciprocally, a depression of PKC epsilon reduces BDNF and MnSOD, resulting in oxidative stress. These changes can be prevented with the PKC epsilon-specific activators.