Alternative Anastrozole Target Protects Neurons in Preclinical Models of Inherited Tauopathy

This study explores the neuroprotective properties of anastrozole, a clinical aromatase inhibitor, in both a Drosophila tauopathy model expressing human MAPTR406W and isogenic pairs of human induced pluripotent stem cell -derived cortical neurons expressing MAPT mutations.

Initially identified through a Drosophila drug screen, anastrozole significantly reduced oxidative stress and Tau phosphorylation in neurons, independent of its aromatase inhibitory action. Further investigation revealed that anastrozole does not exert its protective effects through cholesterol metabolism or aromatase inhibition. Instead, screening in Drosophila identified CYP4V2 as a potential unintended target.