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Finding a path between amyloid-β and tau

Amyloid-β binding to a norepinephrine receptor leads to increase in tau phosphorylation

by Celia Henry Arnaud
January 26, 2020 | A version of this story appeared in Volume 98, Issue 4


Ribbon structure of part of a norepinephrine receptor with an amyloid oligomer bound to an allosteric binding site.
Credit: Sci. Transl. Med.
An amyloid oligomer (green) binds to an allosteric site on a norepinephrine receptor.

Amyloid-β and tau protein are both known to be bad actors in Alzheimer’s disease. But finding a connection between the two has been elusive. Now a team led by Qin Wang of the University of Alabama at Birmingham reports that amyloid-β and tau may be connected via a receptor involved in norepinephrine signaling (Sci. Transl. Med. 2020, DOI: 10.1126/scitranslmed.aay6931). The α2A adrenergic receptor (α2AAR) is elevated in the brains of people with Alzheimer’s and in mouse models of Alzheimer’s. In the new study, amyloid-β oligomers bind to an allosteric site on one of the receptor’s extracellular loops. (Allosteric sites are binding sites that are separate from a receptor’s main binding site and that induce conformational changes in the receptor.) The binding by amyloid-β redirects the norepinephrine signaling so that it activates an enzyme called glycogen synthase kinase 3β (GSK3β), which causes hyperphosphorylation of tau protein. Such highly phosphorylated forms of tau are found in the protein deposits associated with Alzheimer’s. When added along with a drug that binds the main binding site of α2AAR, amyloid-β concentrations as low as 20 nM were enough to alter GSK3β activity. That’s less than 1% of the concentration required to activate GSK3β by amyloid-β alone. In a mouse model of Alzheimer’s, blocking α2AAR slowed down disease progression.


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