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

K 通道氧化介导阿尔茨海默病和 TBI 常见的淀粉样蛋白生成途径

基本信息

批准号：
10532772
负责人：
FEDERICO SESTI
金额：
$ 39.75万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532772
关键词：
3xTg-AD mouse Abeta synthesis Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid Amyloidosis Apoptosis Autopsy Behavioral Biochemistry Brain Brain Injuries Caenorhabditis elegans Cells Clinical Treatment Clinical Trials Dasatinib Disease Epigenetic Process Etiology FDA approved Failure Focal Adhesions Genetic Goals Hippocampus Histocytochemistry Homologous Gene Hour Human Impaired cognition Individual Integrins Laboratory Research Link MAPK8 gene Macromolecular Complexes Mediating Modification Molecular Mus Names Neurodegenerative Disorders Neurons Oxidation-Reduction Oxidative Stress Pathogenicity Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacological Treatment Potassium Channel Predisposition Process Production Proteins Reactive Oxygen Species Recording of previous events Rest Signal Pathway Signal Transduction Testing Time Tissues Toxic effect Translating Trauma Traumatic Brain Injury Tyrosine Vertebrates Voltage-Gated Potassium Channel Work aging hippocampus beta secretase blood-brain barrier permeabilization cancer therapy cognitive function disability drug efficacy efficacy testing experimental study member mouse model nervous system disorder neuroinflammation neuron component neuron loss neurotoxic neurotoxicity normal aging novel novel therapeutic intervention oxidation response stress activated protein kinase therapeutic evaluation tool

项目摘要

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.

电压门控钾（K+）通道亚家族B成员1 （KCNB1）易发生氧化还原。这样