Microglial Kv1.3 Channels as a Potential Target for Alzheimer's Disease

Abstract

Microglia, the major inflammatory cells of the brain, play a pivotal role in the initiation and progression of Alzheimer's Disease (AD) by either clearing amyloid-β deposits through phagocytic activity or by releasing cytotoxic substances and pro-inflammatory cytokines in response to activation by amyloid-β aggregates, including amyloid-β oligomers (AβO). We here propose microglial Kv1.3 channels as a novel pharmacological target for curbing the harmful effects of Aβ-induced microglia activation. Kv1.3 expression increased in cultured microglia in response to stimulation with AβO as determined by electrophysiology, RT-PCR, Western Blotting and immunohistochemistry. Similarly, microglia isolated from the brains of adult 5xFAD mice, a mouse model expressing high levels of Aβ due to trangenes with AD familial mutations, expressed higher levels of Kv1.3 than microglia isolated from the brains of age-matched control mice. We further observed strong Kv1.3 immunoreactivities in microglia associated with amyloid plaques in brains of 5xFAD mice. Proof for the functional importance of Kv1.3 in microglia comes from our observations that the Kv1.3 blocker PAP-1 inhibits AβO-stimulated nitric oxide production as well as microglia-mediated neurotoxicity in dissociated cultures and organotypic brain slices. A 6-week course of daily PAP-1 injections also reduced the degree of microglia activation in 5xFAD mice. In contrast, Kv1.3 blockade with PAP-1 does not affect phagocytosis of Aβ aggregates by microglia. These observations raise the exciting possibility that Kv1.3 blockers might preferentially inhibit microglia mediated neuronal killing without affecting beneficial functions such as scavenging of debris.Supported by NIH (RO1GM076063, RO1AG010129 and R21AG038910) and Alzheimer's Association (NIRG-10-174150).