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β-Amyloid Hijacks Noradrenaline Signal to Activate Pathological GSK3β/tau Cascade

In a new preclinical study, researchers from the University of Alabama at Birmingham found an important missing part of Alzheimer's disease. The relevant research results were published in the journal Science Translational Medicine on January 15, 2020, and the title of the paper was "β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β / tau cascade".

The corresponding author of the paper, Dr. Qin Wang of the University of Alabama at Birmingham, said, "Our study of the potential mechanisms of β-amyloid (Aβ) toxicity provides new insights into clinical translation, which could have a significant impact on future drug design. It identifies the interaction between Aβ and G protein-coupled receptors, which represents an attractive disease-specific therapeutic target for Alzheimer's disease." This newly discovered pathogenesis may also explain why many Alzheimer's disease clinical trials have failed, as they only target the reduction of Aβ protein accumulation in the brain, the culprit for this disease.

Wang said that the accumulation of Aβ oligomers in the brain is generally considered to induce tau protein pathological changes that target and kill neurons in patients with Alzheimer's disease. However, the link between the two is unclear.

Wang and his colleagues found that Aβ oligomers hijacked noradrenaline signals in neurons in the brain, thereby incorrectly redirecting this signal to activate a kinase called GSK3β. This activated kinase then causes high phosphorylation of the tau protein, making it toxic to neurons. This reorientation of the noradrenaline signal occurs on a cell membrane receptor called the alpha-2A adrenergic receptor (α2AAR) on the surface of neurons. This receptor is a G protein-coupled receptor. They found that although certain concentrations of Aβ oligomers can activate GSK3β, the presence of norepinephrine greatly increased the sensitivity of this activation by two orders of magnitude. As a result, these researchers speculate that nanomolar Aβ oligomers in the human brain induce the pathogenic GSK3β/tau cascade in the earliest stages of Alzheimer's disease. This theory suggests that many clinical trials to reduce Aβ oligomer levels in patients with Alzheimer's disease have failed because they were unable to reduce Aβ levels to such low concentrations.

Wang and his colleagues tested an existing drug, idazoxan, in a mouse model of Alzheimer's disease. Idazoxan is an α2AAR antagonist that has been studied in clinical trials of depression. One hypothesis is that in the presence of Aβ pathology, the blockade of α2AAR by idazoxan will show therapeutic potential. From the age of 8 months, these mice were treated with idazoxan for 8 weeks. At the beginning of the treatment, Aβ plaques were already present in their brains, and α2AAR showed enhanced activity. Compared with controls, these researchers found that: (1) idazoxan reversed GSK3β activation in the brains of these mice, further supporting that α2AAR plays a key role in mediating Aβ-induced GSK3β activation in vivo; (2) in the cerebral cortex of a mouse model of Alzheimer's disease treated with idazoxan, the degree of Aβ load is lower, which indicates that blocking α2AAR slows the pathological progression of Aβ; (3) idazoxan treatment reduces the density of inflammatory microglia, which showed a decrease in neuroinflammation; (4) idazoxan treatment can reduce the hyperphosphorylation of tau protein, which shows that blocking α2AAR can effectively relieve Aβ-induced tau pathology; (5) in two cognitive function test, Alzheimer's disease mice treated with idazoxan performed almost as well as normal mice, and were significantly better than untreated mice. "These data collectively confirm that blocking norepinephrine signaling through α2AAR is an effective strategy to alleviate pathological and cognitive deficits associated with Aβ," Wang said.

Wang said, "α2AAR blockers such as idazoxan have been developed to treat other diseases, and switching to these drugs may be a potentially effective strategy for treating Alzheimer's disease. In addition, our data suggest that the interaction between Aβ and α2AAR is an attractive disease-specific therapeutic target for Alzheimer's disease, because the α2AAR/GSK3β/tau cascade can only be activated in the presence of Aβ oligomers.”


  1. Zhang et al.; β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade. Science Translational Medicine, 2020, 12, eaay6931.

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