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

> **NIH NIH R01** · RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL · 2021 · $397,500

## Abstract

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.

## Key facts

- **NIH application ID:** 10062467
- **Project number:** 5R01AG060919-03
- **Recipient organization:** RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
- **Principal Investigator:** FEDERICO SESTI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,500
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062467

## Citation

> US National Institutes of Health, RePORTER application 10062467, Oxidation of K+ channels mediates an amyloidogenic pathway common to Alzheimer's disease and TBI (5R01AG060919-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10062467. Licensed CC0.

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