Finding a path between amyloid-β and tau

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 α_2A adrenergic receptor (α_2AAR) 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 α_2AAR, 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 α_2AAR slowed down disease progression.