The team, which effectively targeted this mechanism in a mouse model of Alzheimer’s, now hopes to replicate the test in humans.
The study, “Oxidation of KCNB1 channels in the human brain and in mouse model of Alzheimer’s disease,” appeared in the journal Cell Death & Disease.
Oxidative stress results from an imbalance between the production and clearance of reactive oxygen species (ROS) – free radicals that may damage DNA, fats and proteins, and whose proliferation is well-known in aging and neurodegenerative diseases such as Alzheimer’s.
One of the proteins oxidized by ROS is KCNB1, a potassium channel, which becomes dysfunctional and accumulates in the cell membrane. Subsequently, more free radicals are produced, inducing apoptosis – or programmed cell death.
Oxidation and increasing amounts of KCNB1 have appeared in a mouse model of Alzheimer’s, suggesting KCNB1’s role in the disorder.
Researchers at New Jersey’s Rutgers Robert Wood Johnson Medical School used a transgenic mouse model as well as brains from deceased Alzheimer’s patients to better understand the role of oxidized KCNB1.
Most previous studies have used animal models only, Federico Sesti, the study’s senior author and a professor of neuroscience and cell biology, noted in a press release.
In the human hippocampus — a critical area for memory — researchers found marked KCNB1 oxidation, as well as increased phosphorylation – activation through the addition of phosphate chemical groups – of FAK and Src kinases, two types of enzymes involved in increased ROS production mediated by accumulated KCNB1.
In mice, KCNB1 oxidation was linked to inflammation and oxidative stress, which increased neuronal levels of the beta-amyloid protein, the main component of senile plaques, and of hyperphosphorylated tau, also a hallmark in Alzheimer’s. In addition, it correlated with deficits in working memory – a form of short-term memory important for reasoning and decision-making.
In turn, transgenic mice that produced a low-oxidation form of KCNB1, researchers observed improvements in working memory and reduced brain inflammation, protein oxidation, beta-amyloid and hyperphosphorylated tau compared to the mouse model of Alzheimer’s and to mice expressing the normal KCNB1 channel.
“This study provides the first experimental evidence that oxidative modification of KCNB1 takes place in the aging human brain and is exacerbated in the Alzheimer’s brain,” researchers wrote.
They then used a leukemia medication called dasatinib — marketed as Sprycel — which is known to ease tissue damage and behavioral deficits in a mouse model of traumatic brain injury.
Compared to prior studies reporting only modest effects in the same transgenic mouse model of Alzheimer’s used by the Rutgers scientists, dasatinib showed increased memory improvements in younger animals undergoing longer treatment.
This proves that KCNB1 oxidation happens early on in Alzheimer’s, investigators observed.
“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,” Sesti said.
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