Summary: A new study reports under conditions of stress, KCNB1 builds up in the brain, before becoming toxic and promoting the production of amyloid beta. In Alzheimer’s patients, the KCNB1 levels are higher than in those without the condition.
Source: Rutgers University.
Rutgers researchers have discovered a new mechanism that may contribute to Alzheimer’s disease and traumatic brain injury. They now hope to launch a clinical trial to test the treatment in humans.
What causes Alzheimer’s is unknown, but a popular theory suggests a protein known as amyloid-beta slowly builds up a plaque in the brains of people with Alzheimer’s. But in a recent study in the journal Cell Death & Disease, Federico Sesti, a professor of neuroscience and cell biology at Rutgers Robert Wood Johnson Medical School, looked at a new mechanism, which involves a non-amyloid-beta protein, a potassium channel referred to as KCNB1.
Under conditions of stress in a brain affected by Alzheimer’s, KCNB1 builds up and becomes toxic to neurons and then promotes the production of amyloid-beta. The build-up of KCNB1 channels is caused by a chemical process commonly known as oxidation.
“Indeed, scientists have known for a long time that during aging or in neurodegenerative disease cells produce free radicals,” said Sesti. “Free radicals are toxic molecules that can cause a reaction that results in lost electrons in important cellular components, including the channels.”
The study found that in brains affected by Alzheimer’s, the build-up of KCNB1 was much higher compared to normal brains.
“The discovery of KCNB1’s oxidation/build-up was found through observation of both mouse and human brains, which is significant as most scientific studies do not usually go beyond observing animals,” said Sesti. “Further, KCBB1 channels may not only contribute to Alzheimer’s but also to other conditions of stress as it was found in a recent study that they are formed following brain trauma.”
In the cases of Alzheimer’s and traumatic brain injury, the build-up of KCNB1 is associated with severe damage of mental function. As a result of this discovery, Sesti successfully tested a drug called Sprycel in mice. The drug is used to treat patients with leukemia.
“Our study shows that this drug and similar ones could potentially be used to treat Alzheimer’s, a discovery that leads the way to launching a clinical trial to test this drug in humans.”
About this neuroscience research article
Source: Jennifer Forbes Mullenhard – Rutgers University Publisher: Organized by NeuroscienceNews.com. Image Source: NeuroscienceNews.com image is in the public domain. Original Research: Open access research for “Oxidation of KCNB1 channels in the human brain and in mouse model of Alzheimer’s disease” by Yu Wei, Mi Ryung Shin & Federico Sesti in Cell Death & Disease. Published July 26 2018. doi:10.1038/s41419-018-0886-1
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[cbtabs][cbtab title=”MLA”]Rutgers University”Possible Cause of Alzheimer’s and TBI Discovered.” NeuroscienceNews. NeuroscienceNews, 26 September 2018. <https://neurosciencenews.com/alzheimers-tbi-mechanism-9922/>.[/cbtab][cbtab title=”APA”]Rutgers University(2018, September 26). Possible Cause of Alzheimer’s and TBI Discovered. NeuroscienceNews. Retrieved September 26, 2018 from https://neurosciencenews.com/alzheimers-tbi-mechanism-9922/[/cbtab][cbtab title=”Chicago”]Rutgers University”Possible Cause of Alzheimer’s and TBI Discovered.” https://neurosciencenews.com/alzheimers-tbi-mechanism-9922/ (accessed September 26, 2018).[/cbtab][/cbtabs]
Oxidation of KCNB1 channels in the human brain and in mouse model of Alzheimer’s disease
Oxidative modification of the voltage-gated K+ channel subfamily B member 1 (KCNB1, Kv2.1) is emerging as a mechanism of neuronal vulnerability potentially capable of affecting multiple conditions associated with oxidative stress, from normal aging to neurodegenerative disease. In this study we report that oxidation of KCNB1 channels is exacerbated in the post mortem brains of Alzheimer’s disease (AD) donors compared to age-matched controls. In addition, phosphorylation of Focal Adhesion kinases (FAK) and Src tyrosine kinases, two key signaling steps that follow KCNB1 oxidation, is also strengthened in AD vs. control brains. Quadruple transgenic mice expressing a non-oxidizable form of KCNB1 in the 3xTg-AD background (APPSWE, PS1M146V, and tauP301L), exhibit improved working memory along with reduced brain inflammation, protein carbonylation and intraneuronal β-amyloid (Aβ) compared to 3xTg-AD mice or mice expressing the wild type (WT) KCNB1 channel. We conclude that oxidation of KCNB1 channels is a mechanism of neuronal vulnerability that is pervasive in the vertebrate brain.