Kv1.3 Inhibition Reduces Amyloid-Beta Induced Microglial Neurotoxicity

The voltage-gated K+ channel Kv1.3 has long been known to play an important role in microglia. Our group recently demonstrated that Kv1.3 expression increases following differentiation into M1-like proinflammatory microglia and that the Kv1.3 inhibitor PAP-1 improves pathology in both mouse and rat models of ischemic stroke. Based on the observation that Kv1.3 expression is elevated in microglia in human Alzheimer's disease (AD) brains we hypothesized that Kv1.3 might constitute an attractive novel target for reducing neuroinflammation in AD. To determine if our in vitro observation of enhanced Kv1.3 expression in M1-like microglia can be generalized to adult microglia, we injected LPS intracerebroventricular (ICV) into WT and Kv1.3-/- mice. Acutely isolated WT CD11+ cells showed increased Kv1.3 current densities and increased inflammatory cytokine production at 24 h. Hippocampal slices acutely obtained from LPS ICV-injected WT mice demonstrated a deficit of LTP in Schaffer-commissural synapses. Kv1.3 knockout completely rectified this hLTP deficit. PAP-1 treatment after LPS-ICV had similar effects. We next evaluated microglial Kv1.3 expression in the 5xFAD mouse model and found that CD11+ cells from 4, 6, and 10 months old 5xFAD mice showed significantly increased Kv1.3 channel activity. In cultured microglia Kv1.3 inhibition with PAP-1 blocked AβO-induced microglia proliferation, p38MAPK phosphorylation, NF-κB activation, and NO generation but not AβO phagocytosis. In hippocampal slice cultures, which allow microglia and neurons to interact, PAP-1 inhibited AβO-induced microglia mediated neuronal killing. We next evaluated PAP-1 in two mouse models of amyloid-induced neuropathology. In mice receiving bilateral intrahippocampal injection of AβO daily oral PAP-1 (50 mg/kg) for 8 days improved performance in the step-through passive avoidance test, while PAP-1 medicated diet administered for 5 months to APP/PS1 mice starting at 9 months of age improved their performance in several tests evaluating memory deficits and reduced the cerebral Aβ-amyloid load and soluble and insoluble Aβ in brain homogenates as determined by ELISA. Taken together our results suggest that Kv1.3 should indeed be further investigated as a potential pharmacological target for the treatment of Alzheimer's disease and other conditions accompanied by neuroinflammation. Supported by NIH (NS098328, AG043788 and AG038910).