Oxidation of K+ channels mediates an amyloidogenic pathway common to Alzheimer's disease and TBI

Project Details

Description

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.
StatusActive
Effective start/end date2/1/1911/30/23

Funding

  • National Institutes of Health: $397,500.00
  • National Institutes of Health: $357,750.00

ASJC

  • Medicine(all)

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