In a new study, researchers have revealed a key missing piece of the Alzheimer’s disease puzzle.
They found an existing drug that dramatically reduced Alzheimer’s pathology and symptoms in two mouse models.
The drug is called idazoxan, and it has been under study in clinical trials for depression.
This may potentially offer immediate treatment for this devastating disease.
The study included human brain tissue analysis and longitudinal clinical data that supported the in vivo mouse model data.
The research was conducted by a team at the University of Alabama at Birmingham.
It is widely accepted that buildup of amyloid-beta oligomers in the brain acts as a trigger to induce pathological changes in tau protein, and that altered tau protein is the bullet that targets and kills neurons in Alzheimer’s disease.
However, the pathway connecting these two was unknown.
The team found that amyloid-beta oligomers hijack norepinephrine signaling at brain neurons, which falsely redirects this signal to activate a kinase called GSK3-beta.
That activated kinase enzyme, in turn, hyper-phosphorylates tau protein, making it toxic for neurons.
The team speculated that nanomolar concentrations of amyloid-beta oligomers in human brains induce a pathogenic GSK3-beta/tau cascade at the earliest stages of Alzheimer’s disease.
This theory suggests why multiple clinical trials to reduce levels of amyloid-beta oligomers in Alzheimer’s disease patients have failed—they cannot reduce the amyloid levels to such low concentrations.
The team also found that taking the drug clonidine—an activator of alpha-2A adrenergic receptor used to lower blood pressure—worsened cognitive function in patients with cognitive deficits.
Furthermore, the adverse effects of clonidine were stronger in patients with more severe dementia. Clonidine usage had no effect on people with normal cognition.
The team also tested an existing drug—idazoxan—in a mouse model of Alzheimer’s.
The hypothesis was that idazoxan blockage of alpha-2A adrenergic receptor in the presence of amyloid-beta pathology would show therapeutic potential.
The findings confirmed the hypothesis and suggested that repurposing idazoxan could be a potentially effective, readily available strategy for Alzheimer’s disease treatment.
One author of the study is Qin Wang, M.D., Ph.D.
The study is published in the journal Science Translational Medicine.
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