The voltage-gated potassium (K+) channel sub-family B member 1 (KCNB1) is susceptible to redox. As such oxidative modification of this channel has the potential to occur under, and consequently to impact, a number of conditions associated with oxidative stress. Accordingly, oxidized KCNB1 channels are present in the post mortem human hippocampi of aging donors and in significantly larger amounts in the hippocampi of Alzheimer's disease (AD) donors. KCNB1 oxidation increases neuronal loss and impairs cognitive function in mouse models of AD (3xTg-AD background) and traumatic brain injury (TBI). These two conditions are associated with multiple etiologies and pathogenic mechanisms but share robust oxidative stress. Moreover, the toxic effects associated with oxidation of the KCNB1 channels are moderated by Dasatinib, a FDA-approved drug. The broad goal of this proposal is to elucidate the molecular basis for the neurotoxic effects of KCNB1 oxidation. We will test two consequential hypotheses. First, that oxidized KCNB1 channels promote neurotoxicity through the Stress Activated Protein Kinase (SAPK) pathway. Second, that KCNB1-mediated activation of SAPK signaling provides a common amyloidogenic pathway in the AD and the TBI brains, by increasing b-amyloid production via direct and/or indirect dysregulation of the activities of the b-secretase (BACE1). We will test these hypotheses by the means of genetics, behavioral analysis, biochemistry and histochemistry. If successful, this work will: 1) advance our understanding of a widespread mechanism of neuronal vulnerability; 2) elucidate a new pathway for amyloidosis common to AD and TBI, that was not considered before and 3) may indicate novel therapeutic approaches that could be translated into clinical trials.
Neurological diseases cause devastating disabilities affecting millions of individuals each year but unfortunately, effective pharmacological treatments for these pathologies do not exist. The goal of this project is to elucidate a common mechanism of neurotoxicity mediated by a class of proteins critical for neuronal function and survival: the potassium channels. We will study how potassium channels promote neuronal loss, tissue damage and cognitive impairment in two major neurological diseases, Alzheimer's disease and Traumatic Brain Injury and will we will test the therapeutic potential of a FDA-approved drug that impinges on the neuronal components that directly interact and are activated by, potassium channels in mice.
