Summary: New research finds that under conditions of cellular stress, the potassium channel KCNB1 accumulates in the brain, becomes toxic to neurons, and promotes the production of amyloid‑beta. Levels of oxidized KCNB1 are higher in brains of people with Alzheimer’s disease than in those without the condition.
Source: Rutgers University.
Rutgers researchers identify a non‑amyloid mechanism that may contribute to Alzheimer’s disease and traumatic brain injury; preclinical drug testing suggests a potential therapeutic path.
Alzheimer’s disease remains without a definitive cause, though accumulation of amyloid‑beta plaques has long been a leading hypothesis. A recent study published in the journal Cell Death & Disease by Federico Sesti and colleagues at Rutgers Robert Wood Johnson Medical School describes a complementary mechanism that may drive neuronal damage: oxidation and buildup of the voltage‑gated potassium channel KCNB1 (also known as Kv2.1).
The research shows that under oxidative stress—commonly seen in aging and neurodegenerative conditions—KCNB1 channels undergo chemical modification that leads to their aggregation in neurons. These oxidized KCNB1 aggregates are neurotoxic and appear to promote processes that increase amyloid‑beta production, linking channel oxidation to established Alzheimer’s pathology.
“It has long been recognized that aging and neurodegenerative disease are accompanied by increased production of reactive oxygen species,” said Sesti. “Those free radicals can damage cellular components, including ion channels, and our findings show that KCNB1 oxidation is pronounced in Alzheimer’s brain tissue.”
The investigators examined both human post‑mortem brain samples and mouse models. They report that oxidized KCNB1 and downstream activation of signaling kinases such as FAK and Src are significantly increased in Alzheimer’s brains compared with age‑matched controls. This is notable because many preclinical studies focus only on animal models; the combination of human and mouse data strengthens the translational relevance.
To probe causality, the team used genetically modified mice: a quadruple transgenic line in which a non‑oxidizable form of KCNB1 was expressed in an Alzheimer’s disease model background (3xTg‑AD). These mice showed improved working memory and reduced markers of brain inflammation, protein carbonylation (a marker of oxidative damage), and intraneuronal amyloid‑beta compared with animals expressing the wild‑type channel or standard 3xTg‑AD mice. The results suggest that preventing KCNB1 oxidation can mitigate several pathological features associated with Alzheimer’s.
Beyond Alzheimer’s, the study highlights that KCNB1 channel oxidation and aggregation also occur after traumatic brain injury (TBI), indicating a broader role for this mechanism in brain stress responses. In both TBI and Alzheimer’s, KCNB1 buildup correlates with worse cognitive outcomes, suggesting the channel’s oxidation may be a convergent pathway of neuronal vulnerability across conditions marked by oxidative stress.
Building on these findings, Sesti and colleagues evaluated a pharmacological approach in mice using dasatinib (marketed as Sprycel®), a tyrosine kinase inhibitor approved for certain leukemias. In preclinical tests the drug reduced some of the harmful signaling associated with oxidized KCNB1 and improved outcomes in mouse models. While promising, the researchers emphasize that human clinical trials are necessary to determine safety and efficacy for Alzheimer’s or TBI patients, and they hope to initiate such trials in the future.
Source: Rutgers University.
Publisher: Organized and reported by NeuroscienceNews.com.
Image source: Rutgers University / NeuroscienceNews.com (public domain).
Original research: Yu Wei, Mi Ryung Shin & Federico Sesti. “Oxidation of KCNB1 channels in the human brain and in mouse model of Alzheimer’s disease.” Cell Death & Disease, published July 26, 2018.
DOI: 10.1038/s41419-018-0886-1
Oxidation of KCNB1 channels in the human brain and in mouse model of Alzheimer’s disease
Oxidative modification of KCNB1 (Kv2.1) is emerging as a mechanism of neuronal vulnerability that may affect conditions associated with oxidative stress, from normal aging to neurodegenerative disease. This study reports that KCNB1 oxidation is increased in post‑mortem Alzheimer’s disease donor brains versus age‑matched controls. Phosphorylation of focal adhesion kinase (FAK) and Src tyrosine kinases—key steps that follow KCNB1 oxidation—is also elevated in Alzheimer’s brains. Quadruple transgenic mice expressing a non‑oxidizable KCNB1 in the 3xTg‑AD background exhibited improved working memory and reduced brain inflammation, protein carbonylation, and intraneuronal amyloid‑beta relative to control 3xTg‑AD mice or mice expressing wild‑type KCNB1. These results support the conclusion that KCNB1 oxidation is a widespread mechanism of neuronal vulnerability in the vertebrate brain.
This research identifies KCNB1 oxidation as a potential therapeutic target for Alzheimer’s disease and traumatic brain injury. Preclinical drug testing in mice supports further investigation, but clinical trials are required to determine if targeting KCNB1 oxidation is effective and safe in humans.